NZ714931A - Nuclear transport modulators and uses thereof - Google Patents

Abstract

The present invention relates to compounds of formula IV: and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds of formula IV or their pharmaceutically acceptable salts, and methods of using said compounds, salts and compositions in the treatment of various disorders associated with CRM1 activity.

Description

NUCLEAR TRANSPORT MODULATORS AND USES THEREOF RELATED APPLICATION This application claims the benefit of US. Provisional Application No. ,172, filed on June 21, 2013. The entire teachings of this application are incorporated herein by reference.

BACKGROUND OF THE INVENTION Cells from most major human solid and hematologic malignancies exhibit abnormal ar localization of a y of oncogenic ns, tumor suppressor proteins, and cell cycle regulators (Cronshaw et al, 2004, Falini et al 2006). For example, certain p53 mutations lead to localization in the cytoplasm rather than in the nucleus. This results in the loss of normal growth regulation, despite intact tumor suppressor function. In other tumors, wild—type p53 is sequestered in the cytoplasm or rapidly degraded, again g to loss of its suppressor function. Restoration of appropriate nuclear localization of functional p53 protein can normalize some properties of neoplastic cells (Cai et al, 2008; Hoshino et al 2008; Lain et al 1999a; Lain et al 1999b; Smart et al 1999), can restore sensitivity of cancer cells to DNA damaging agents (Cai et al, 2008), and can lead to regression of established tumors (Sharpless & DePinho 2007, Xue et al, 2007). Similar data have been obtained for other tumor suppressor proteins such as forkhead r and Sullivan 2008) and c—Abl ri and Wang 2001). In addition, abnormal localization of several tumor suppressor and growth regulatory proteins may be involved in the pathogenesis of autoimmune diseases (Davis 2007, Nakahara 2009). CRMl inhibition may provide particularly interesting utility in familial cancer syndromes (e.g., Li—Fraumeni Syndrome due to loss of one p53 , BRCAl or 2 cancer syndromes), where specific tumor ssor proteins (TSP) are deleted or dysfunctional and where increasing TSP levels by systemic (or local) administration of CRMl inhibitors could help restore normal tumor ssor function.

Specific proteins and RNAs are carried into and out of the s by lized transport molecules, which are classified as importins if they transport molecules into the nucleus, and exportins if they transport molecules out of the nucleus (Terry et al, 2007; WO 05389 Sorokin et al 2007). Proteins that are transported into or out of the nucleus contain nuclear import/localization (NLS) or export (NES) sequences that allow them to interact with the relevant transporters. Chromosomal Region Maintenance 1 (Crml), which is also called exportin—l or Xpol, is a major exportin.

Overexpression of Crml has been reported in l tumors, including human ovarian cancer (Noske et al, 2008), cervical cancer (van der Watt et al, 2009), atic cancer (Huang et al, 2009), hepatocellular carcinoma (Pascale et al, 2005) and osteosarcoma (Yao et al, 2009) and is ndently correlated with poor clinical outcomes in these tumor types.

Inhibition of Crml blocks the exodus of tumor suppressor proteins and/or growth regulators such as p53, c-Abl, p21, p27, pRB, BRCAl, IkB, ICp27, E2F4, KLFS, YAPl, ZAP, KLFS, HDAC4, HDACS or forkhead proteins (e.g. FOXO3 a) from the nucleus that are ated with gene expression, cell proliferation, angiogenesis and epigenetics. Crml inhibitors have been shown to induce apoptosis in cancer cells even in the presence of activating oncogenic or growth stimulating signals, while sparing normal (untransformed) cells. Most studies of Crml inhibition have utilized the natural product Crml inhibitor ycin B (LMB). LMB itself is highly toxic to neoplastic cells, but poorly tolerated with marked gastrointestinal toxicity in animals ts et al, 1986) and humans (Newlands et al, 1996). Derivatization of LMB to improve drug—like properties leads to compounds that retain antitumor activity and are better tolerated in animal tumor models (Yang et al, 2007, Yang et al, 2008, Mutka et al, 2009). Therefore, nuclear export inhibitors could have beneficial effects in neoplastic and other proliferative disorders. To date, however, small- molecule, drug—like Crml inhibitors for use in vitro and in vivo are uncommon.

In addition to tumor suppressor ns, Crml also exports several key proteins that are involved in many inflammatory processes. These include IkB, NF-kB, Cox-2, RXROL, Commdl, HIFl, HMGBl, FOXO, FOXP and others. The nuclear factor kappa B (NF—kB/rel) family of transcriptional activators, named for the discovery that it drives immunoglobulin kappa gene expression, regulate the mRNA expression of variety of genes involved in inflammation, proliferation, immunity and cell al. Under basal conditions, a protein inhibitor B, called IkB, binds to NF—kB in the nucleus and the complex IkB-NF-kB renders the NF—kB transcriptional function inactive. In response to inflammatory stimuli, IkB dissociates from the IkB-NF—kB complex, which es NF—kB and unmasks its potent transcriptional activity. Many signals that activate NF-kB do so by targeting IkB for proteolysis (Phosphorylation of IkB renders it "marked" for ubiquitination and then proteolysis). The nuclear IkBa—NF-kB complex can be exported to the cytoplasm by Crml where it dissociates and NF-kB can be reactivated. Ubiquitinated IkB may also dissociate from the NF-kB x, restoring NF—kB riptional activity. Inhibition of Crml induced export in human neutrophils and macrophage like cells (U937) by LMB not only s in accumulation of transcriptionally inactive, nuclear IkBa-NF-kB complex but also prevents the initial activation of NF-kB even upon cell stimulation (Ghosh 2008, Huang 2000). In a different study, treatment with LMB inhibited IL-1 [3 induced NF—kB DNA binding (the first step in NF—kB transcriptional activation), IL—8 expression and intercellular adhesion molecule expression in ary microvascular endothelial cells (Walsh 2008).

COMMDl is another nuclear inhibitor of both NF—kB and hypoxia-inducible factor 1 (HIFl) transcriptional activity. Blocking the nuclear export of COMMDl by inhibiting Crml results in increased tion of NF—kB and HIFl riptional activity (Muller 2009).

Crml also mediates Retinoid X receptor 0t (RXROL) transport. RXROL is highly expressed in the liver and plays a l role in regulating bile acid, cholesterol, fatty acid, steroid and xenobiotic metabolism and homeostasis. During liver inflammation, nuclear RXROL levels are significantly reduced, mainly due to inflammation—mediated nuclear export of RXROL by Crml. Lep B is able to prevent IL—lB induced asmic se in RXROL levels in human liver derived cells (Zimmerman 2006).

The role of ediated nuclear export in NF-kB, HIF-l and RXROL signalling suggests that blocking r export can be potentially beneficial in many inflammatory processes across multiple tissues and organs including the vasculature litis, arteritis, polymyalgia rheumatic, atherosclerosis), dermatologic (see above), tologic (rheumatoid and related arthritis, psoriatic arthritis, loarthropathies, l arthropathies, systemic lupus erythematosus, mixed connective tissue disease, myositis syndromes, dermatomyositis, inclusion body myositis, undifferentiated connective tissue disease, Sjogren’s syndrome, scleroderma and overlap syndromes, etc.).

CRMl Inhibition affects gene expression by inhibiting/activating a series of transcription factors like ICp27, E2F4, KLFS, YAPl, ZAP Crml inhibition has potential therapeutic effects across many dermatologic mes including inflammatory dermatoses (atopy, allergic dermatitis, chemical dermatitis, psoriasis), sun—damage (Ultraviolet / UV damage), and infections. CRMl inhibition, best studied with LMB, showed l effects on normal keratinocytes, and exerted anti—inflammatory activity on keratinocytes ted to UV, TNFa, or other inflammatory stimuli (Kobayashi & Shinkai 2005, Kannan & Jaiswal 2006). Crml tion also upregulates NRF2 (nuclear factor oid-related factor 2) activity, which protects keratinocytes (Schafer et al, 2010, Kannan & Jaiswal 2006) and other cell types (Wang et al, 2009) from oxidative damage. LMB s apoptosis in keratinocytes infected with oncogenic human papillomavirus (HPV) strains such as HPV16, but not in uninfected keratinocytes (Jolly et al, 2009).

Crml also mediates the transport of key neuroprotectant proteins that may be useful in neurodegenerative diseases including Parkinson’s Disease (PD), Alzheimer’s Disease, and Amyotrophic Lateral Sclerosis. For example, (1) forcing nuclear retention of key neuroprotective regulators such as NRF2 (Wang 2009), FOXA2 (Kittappa et a1, 2007), parking in neuronal cells and/or by (2) inhibiting NFKB transcriptional activity by sequestering IKB to the nucleus in glial cells, Crml tion could slow or prevent neuronal cell death found in these disorders. There is also evidence linking abnormal glial cell proliferation to abnormalities in CRMl levels or CRl function (Shen 2008).

Intact nuclear export, primarily mediated through CRMl, is also required for the intact tion of many viruses. Viruses where nuclear export, and/or CRMl , has been implicated in their lifecycle include human immunodeficiency virus (HIV), adenovirus, simian retrovirus type 1, Borna disease virus, za (usual strains as well as H1N1 and avian H5Nl strains), hepatitis B (HBV) and C (HCV) viruses, human papillomavirus (HPV), respiratory syncytial virus (RSV), Dungee, Severe Acute atory me coronavirus, yellow fever virus, West Nile Virus, herpes simplex virus (HSV), cytomegalovirus (CMV), and Merkel cell polyomavirus (MCV). (Bhuvanakantham 2010, Cohen 2010, Whittaker 1998). It is anticipated that additional viral infections t on intact nuclear export will be uncovered in the near future.

The HIV-l Rev protein, which traffics through nucleolus and shuttles between the nucleus and cytoplasm, tates export of unspliced and singly spliced HIV transcripts containing Rev Response ts (RRE) RNA by the CRMI export pathway. Inhibition of Rev-mediated RNA transport using CRMI inhibitors such as LepB or PKF050-638 can arrest the HIV—1 transcriptional process, inhibit the production of new HIV-1 virions, and thereby reduce HIV-1 levels (Pollard 1998, Daelemans 2002).

Dengue virus (DENV) is the causative agent of the common pod—borne viral disease, dengue fever (DF), and its more severe and potentially deadly dengue hemorrhagic fever (DHF). DHF appears to be the result of an over exuberant inflammatory response to DENV. N85 is the largest and most conserved protein of DENV. CRMl regulates the transport of N85 from the nucleus to the asm, where most of the NSS functions are mediated. Inhibition of CRMl mediated export ofN85 results in altered cs of virus production and reduces induction of the atory ine interleukin-8 (IL—8), presenting a new avenue for the treatment of diseases caused by DENV and other medically important flaviviruses including Hepatitis C virus (Rawlinson 2009).

Other virus—encoded RNA—binding proteins that use CRMl to exit the nucleus include the HSV type 1 nt protein (VP13/ 14, or hUL47), human CMV protein pp65, the SARS Coronavirus ORF 3b Protein, and the RSV matrix (M) protein ams 2008, Sanchez 2007, Freundt 2009, Ghildyal 2009). stingly, many of these viruses are associated with specific types of human cancer including hepatocellular carcinoma (HCC) due to chronic HBV or HCV infection, cervical cancer due to HPV, and Merkel cell carcinoma associated with MCV. CRMl tors could therefore have beneficial effects on both the viral infectious process as well as on the process of neoplastic transformation due to these s.

CRMl controls the nuclear localization and therefore activity of multiple DNA metabolizing enzymes including histone ylases (HDAC), histone acetyltransferases (HAT), and histone transferases (HMT). Suppression of cardiomyocyte hypertrophy with irreversible CRMl inhibitors has been demonstrated and is believed to be linked to nuclear retention (and activation) of HDAC 5, an enzyme known to suppress a hypertrophic genetic program (Monovich et al, 2009). Thus, CRMl inhibition may have beneficial effects in hypertrophic mes, including n forms of congestive heart failure and hypertrophic cardiomyopathies.

CRMl has also been linked to other disorders. Leber’s disorder, a hereditary disorder characterized by degeneration of retinal ganglion cells and visual loss, is associated with inaction of the CRMl switch (Gupta N 2008). There is also evidence linking neurodegenerative disorders to abnormalities in nuclear transport.

WO 05389 In view of the above, the discovery of compounds that modulate nuclear transport is desirable.

SUMMARY OF THE INVENTION The present invention relates to compounds, and pharmaceutically acceptable salts thereof, useful as r transport tors; ceutically acceptable compositions comprising compounds of the present invention or their ceutically able salts; and methods of using said compounds, salts and compositions in the treatment of various disorders.

The compounds of the invention have general formula I: CH3"R)n\ \ "1)in (I), wherein each variable is as defined and described herein.

Compounds of the present invention and ceutically acceptable salts and itions thereof are usefiil for treating a variety of diseases, disorders or conditions associated vvith abnormal cellular responses red by improper nuclear transport.

Therefore, one embodiment of the invention is use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treating a variety of es, disorders or conditions associated with abnormal cellular responses triggered by improper nuclear transport. Another embodiment of the invention is a method for ng a variety of diseases, disorders or conditions associated With CRMl activity in a subject in need thereof, the method sing administering to the subject in need thereof a therapeutically effective amount of a compound the invention, or a pharmaceutically able salt or composition thereof. Such diseases, disorders, or conditions include those bed herein.

Compounds of the invention, and pharmaceutically acceptable salts thereof, are also useful in the manufacture of a medicament for the treatment of a variety of diseases, disorders or conditions associated With al cellular responses triggered by improper nuclear transport. Such diseases, disorders, or conditions include those described herein.

Compounds provided by this invention are also useful for the study of nuclear transport modulation in biological and pathological phenomena; the study of intracellular WO 05389 signal uction pathways mediated by, for example, kinases; and the comparative evaluation of new nuclear transport modulators.

BRIEF DESCRIPTION OF THE FIGURES The foregoing will be apparent from the following more particular description of example embodiments of the invention. is an image of a n blot, and shows that treatment of HT1080 cells with Compound 124 results in a dose-dependent degradation of CRMl. is a graph of mean clinical score for all paws in the CAIA mouse model of rheumatoid arthritis described in Example 3 as a function of study day, and shows the effect of treatment with vehicle only and nd 124 on mean clinical scores for all paws of mice in the study. is a graph of mean tumor volume as a function of time, and shows the effects of treatment with Compound 124 or Compound 149 on mean tumor volume in mice bearing MDA-MB-468 afts. is a graph of mean tumor volume as a function of time, and shows the effects of treatment with Compound 124 (5 mg/kg or 15 mg/kg) or cyclophosphamide on mean tumor volume in mice bearing Z-13 8 xenografts. is a graph of mean tumor volume as a fiinction of time, and shows the effects of treatment with Compound 124 (5 mg/kg or 15 mg/kg) or doxorubicin on mean tumor volume in mice bearing Hep 3B xenografts. is a graph of mean tumor volume as a function of time, and shows the effects of ent with Compound 124 (5 mg/kg or 15 mg/kg) or 5-FU on mean tumor volume in mice bearing COLO 205 xeno grafts. is a graph of mean tumor volume as a function of time, and shows the effects of treatment with Compound 124 (5 mg/kg or 15 mg/kg) or doxorubicin on mean tumor volume in mice bearing MOLT 4 xenografts. are images of U87MG and U251MG control spheroids and U87MG and U251MG spheroids d with 1 uM Compound 124, and shows the effects of treatment with Compound 124 on two glioblastoma cell lines.

DETAILED DESCRIPTION OF THE INVENTION Compounds ofthe Invention A first embodiment of the invention is a compound of structural formula I: ( R1 )n \<_:\>_ In a first aspect of the first embodiment, one of R21 and Rb is hydrogen, and the other is selected from —C(O)—O—R3, —C(O)-N(R5)(R6), —C(O)—N(R7)—N(R5)(R6), ~C(O)—N(R7)-N(R7)—C(O)—R4 and N(R7)—N(R7)-S(O)1_2—R4. The values for the remaining variables are as described in the first ment.

In a second aspect of the first embodiment, one of R21 and Rb is hydrogen, and the other is selected from -C(O)—OH, -C(O)—NH2, —C(O)-N(R7)-N(R5)(R6), —C(O)-N(R7)-N(R7)-C(O)-R4 and -C(O)—N(R7)—N(R7)-S(O)1.2—R4. The values for the remaining variables are as described in the first embodiment, or first aspect thereof.

In a third aspect of the first embodiment, one of R21 and Rb is hydrogen, and the other is —C(O)-OH; or-C(O)-NH2; or —C(O)—NH—NH(R6), and R6 is an optionally substituted heteroaryl; or NH-NH—C(O)—R4 or —C(O)-NH—NH—S(O)1_2-R4, and R4 is ed from optionally substituted —N(H)(C3—C6 cycloalkyl), -N(C1—C4 alkyl)(C3—C6 cycloalkyl), —C1-C6 alkyl, —(C0-C4 alkylene)—heterocyclyl and —(C0—C4 alkylene)—heteroaryl. The values for the remaining variables are as described in the first embodiment, or first or second aspect thereof.

In a fourth aspect of the first embodiment, one of Ra and Rh is hydrogen and the other is H2. The values for the remaining variables are as bed in the first embodiment, or first through third aspects thereof.

In a fifth aspect of the first embodiment, R21 is hydrogen. The values for the remaining les are as described in the first embodiment, or first through fourth aspects thereof.

In a sixth aspect of the first embodiment, R2 is an optionally substituted C5—C5 heteroaryl. The values for the remaining variables are as described in the first embodiment, or first through fifth aspects thereof In a seventh aspect of the first embodiment, R2 is an ally substituted 5-6— membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The values for the remaining variables are as bed in the first embodiment, or first through sixth aspects thereof.

In an eighth aspect of the first embodiment, R2 is an optionally substituted 5— membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of en, oxygen and sulfur. The values for the remaining variables are as described in the first embodiment, or first through h aspects thereof.

In a ninth aspect of the first embodiment, R2 is an ally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl. The values for the remaining variables are as described in the first embodiment, or first through eighth aspects thereof.

In a tenth aspect of the first embodiment, R2 is an optionally substituted 6— membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of en, oxygen and sulfur. The values for the remaining variables are as described in the first embodiment, or first through ninth aspects thereof.

In an eleventh aspect of the first embodiment, R2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl. The values for the remaining les are as described in the first embodiment, or first through tenth s thereof.

In a h aspect of the first embodiment, R2 is optionally substituted With halogen, C1—C4 alkyl, C1-C4 alkoxy, C1—C4 thioalkoxy, hydroxyl, amino, C1-C4 alkylamino, C1—C4 dialkylamino, sulfhydryl or cyano. The values for the remaining variables are as described in the first embodiment, or first through eleventh aspects thereof.

In a thirteenth aspect of the first embodiment, R2 is optionally tuted With n, C1—C4 alkyl or C1—C4 alkoxy. The values for the remaining variables are as described in the first embodiment, or first through h aspects thereof.

In a fourteenth aspect of the first embodiment, X is . The values for the remaining variables are as bed in the first embodiment, or first through enth aspects thereof.

In a fifteenth aspect of the first embodiment, n is 0, 1 or 2. The values for the remaining variables are as described in the first embodiment, or first through fourteenth aspects thereof In a sixteenth aspect of the first embodiment, each R1 is independently selected from ~CF3, —CN, halo, — OH, C1-C3 alkyl, C3-C6 cycloalkyl, C3—C12 heterocycloalkyl, halo—C1- C3 alkyl, —NH2, -N02, -NH(C1—C3 alkyl), -N(C1-C3 (C1—C3 alkyl), -C(O)OH, —C(O)O—(C1—C6 alkyl), —C(O)-(C1-C3 alkyl), —O-(C1-C3 alkyl), -O—(C1—C3 haloalkyl), and —S-( C1-C3 alkyl), or is absent. The values for the remaining variables are as described in the first embodiment, or first h th aspects thereof.

In a seventeenth aspect of the first ment, each R1 is independently selected from halo, —C1—C4 alkyl, —C1-C4 haloalkyl and -O-C1-C4 alkyl, or is absent. The values for the remaining variables are as described in the first embodiment, or first through nth aspects thereof.

In an eighteenth aspect of the first ment, one of R3 and Rb is hydrogen, and the other is -C(O)OH; or-C(O)NH2; or -C(O)—NH—NH(R6), and R6 is an optionally substituted (:5—(36 heteroaryl; or —C(O)—NH—NH—C(O)-R4 or -C(O)-NH—NH-S(O)1_2-R4, and R4 is selected from Optionally substituted —N(H)(C3—C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6 cycloalkyl), —C1— C6 alkyl, —(C0—C4 alkylene)—(C3—C7)heterocyclyl and —(Co-C4 alkylene)-(C5-C6)heteroaryl. The values for the remaining variables are as described in the first embodiment, or first through seventeenth aspects thereof.

In a nineteenth aspect of the first embodiment, each R7 is hydrogen. The values for the remaining variables are as described in the first embodiment, or first h eighteenth aspects f.

In a twentieth aspect of the first embodiment, R5 is selected from hydrogen and C1—C4 alkyl; and R6 is selected from C1—C4 alkyl, yclyl, aryl, heterocyclyl and heteroaryl. The values for the remaining variables are as described in the first embodiment, or first through nineteenth aspects thereof.

In a twenty-first aspect of the first embodiment, R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl.

The values for the remaining variables are as described in the first embodiment, or first h eth aspects thereof.

In a twenty-second aspect of the first embodiment, R3 is selected from optionally substituted C1-C4 alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryl. The values for the remaining variables are as described in the first embodiment, or first through twenty-first s thereof.

In a twenty—third aspect of the first embodiment, R4 is selected from -N(R8)(C3-C6 cycloalkyl), —C3-C6 alkyl, {Co—C] alkylene)~heterocyclyl, and {Co—C1 alkylene)—heteroaryl, wherein R8 is hydrogen or ~C1—C4 alkyl, any alkyl or alkylene n of R4 is optionally and independently substituted with one or more substituents ed from the group ting of oxo and —N(R9)2, wherein each R9 is independently selected from hydrogen and C1—C4 alkyl; any heterocyclyl portion of R4 comprises at least one nitrogen atom in a ring, and is Optionally substituted with one or more substituents selected from the group consisting of C1— C4 alkyl and oxo, and any heteroaryl portion of R4 comprises at least one nitrogen atom in a ring and is optionally substituted with one or more C1-C4 alkyl. The values for the remaining variables are as bed in the first embodiment, or first through twenty—second aspects thereof.

In a —fourth aspect of the first embodiment, R2 is optionally tuted with 1, 2 or 3 substituents ndently selected from halogen, C1-C4 alkyl, halo-Cl-C4 alkyl, C1- C4 alkoxy, C1—C4 thioalkoxy, hydroxyl, amino, C1-C4 alkylamino, C1—C4 dialkylamino, sulfhydryl, cyano, C6 aryl and C5—C6 heteroaryl. Values for the variables are as described in the first embodiment, or first through twenty—third aspects f.

In a twenty—fifth aspect of the first embodiment, R2 is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C1-C4 alkyl, -CF3, amino and cyano. Values for the variables are as described in the first embodiment, or first through -fourth s thereof.

A second embodiment of the invention is a compound of structural formula 11: R13 R3 /N INJV Rb, Nsx R2 m (11>, or a pharmaceutically acceptable salt thereof, wherein: R1a and R11) are each independently selected from halo; haloalkyl; —(CH2)1_4R°; —(CH2)0_4OR°; -O—(CH2)0_4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0_4SR°; -(CH2)0carbocyclyl, which may be substituted with R°; -(CH2)0.4-aryl, which may be substituted with R°; —(CH2)0heterocyclyl, which may be substituted with R0; -(CH2)0heteroaryl, which may be substituted with R0; -CH=CH—carbocyclyl, which may be substituted with R°; -CH=CH—aryl, which may be substituted with R0; -CH=CH~heterocyc1y1, which may be substituted with R°; -CH=CH-heteroaryl, which may be substituted with R0; -N02; —CN; -N3; 0_4N(R0)2; -(CH2)0_4N(R°)C(O)R°; 0-4N(R°)C(S)R°; ~(CHz)0—4N(R°)C(OWRO2; "(CH2)o—4N(R°)C(S)NR02; '(CH2)0—4N(R°)C(O)OR°; '(CHz)o-4N(R°)N(R°)C(O)R°; '(CH2)0-4N(RO)N(RO)C(O)NR°2; '(CHz)0-4N(R°)N(R°)C(O)OROQ ~(C1L12)0—4C(O)R°; ’(CH2)0-4C(S)R°; '(CH2)0—4C(O)OR°; '(CH2)0-4C(O)SR°; ‘(CH2)0-4OC(O)RO§ '(CH2)0-4OC(O)(CH2)o—4SR°a '(CH2)0—4SC(S)SRO; '(CH2)0—4SC(O)R°; ~(CH2)0_4C(O)NR°2; 0_4C(S)NR°2; -(CH2)0_4C(S)SRO; -(CH2)0_4OC(O)NR°2; o-4C(O)N(OR°)R°; -(CH2)o—4C(O)C(O)R°; 0_4C(O)CH2C(O)R°; -(CH2)0-4C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0_4S(O)2R°; -(CH2)MS(O)20R°; -(CH2)0_4OS(O)2R°; -(CH2)0-4S(O)2NR°2; -(CH2)0_4S(O)R°; '(CH2)o-4N(R°)S(O)2NR°2; '(CH2)o-4N(R°)S(O)2R°; '(CH2)o-4N(OR°)R°; "(CH2)o-4C(NH)NR°2; "(CH2)o-4P(O)2R°; ~(CH2)o-4P(O)R°2; *(CH2)o-4OP(O)R°2; -(CH2)0-4OP(O)(OR°)2; ~(CH2)O_4ON(R°)2; and 0-4C(O)O-N(R°)2, wherein: each R° is independently hydrogen, C1_6 aliphatic, -CH2—carbocyclyl, -CH2-aryl, ~CH2-heterocyclyl, ~CH2-heteroaryl, -O(CH2)0_1—carbocyclyl, ~O(CH2)O-1~aryl, -O(CH2)0-1—heterocyclyl, —O(CH2)0_1-heteroaryl, carbocyclyl, aryl, heterocyclyl or heteroaryl, or two independent occurrences of R°, taken together with their intervening ), form a 3—12—membered carbocyclyl, aryl, heterocyclyl or hetero aryl; and each R° and each ring formed from two independent occurrences of R°, taken together with their intervening atom(s), are optionally and independently substituted with one or more substituents selected from the group ting of halo, CN, OH, unsubstituted C1—C3 alkyl, halo—Cl-C3 alkyl, —NH2, —NOZ, -NH(unsubstituted C1—C3 alkyl), ubstituted C1-C3 alkyl);, -O—C1—C3 alkyl, -C(O)OH, —C(O)O-(unsubstituted C1-C3 alkyl), -C(O)-(unsubstituted C1—C3 alkyl), -O-(unsubstituted C1-C3 alkyl), and ~S—(unsubstituted C1—C3 alkyl); and m is O or 1.

The values for the remaining variables are as described in the first embodiment, or any aspect thereof.

In a first aspect of the second embodiment, m is 1. The values for the remaining variables are as bed in the first embodiment, or any aspect thereof, or the second embodiment.

In a second aspect of the second ment, R1a is halo or —C1—C4 haloalkyl. The values for the remaining variables are as described in the first embodiment, or any aspect thereof, or the second embodiment, or first aspect thereof.

In a third aspect of the second embodiment, R1a is ~C1—C4 haloalkyl. The values for the ing variables are as described in the first embodiment, or any aspect f, or the second embodiment, or first or second aspect thereof.

In a fourth aspect of the second embodiment, R1b is -C1-C4 haloalkyl or -O-C1-C4 alkyl. The values for the ing variables are as described in the first embodiment, or any aspect thereof, or the second embodiment, or first h third aspects thereof.

In a fifth aspect of the second embodiment, R11) is -C1-C4 haloalkyl. The values for the remaining variables are as described in the first embodiment, or any aspect thereof, or the second embodiment, or first through fourth aspects thereof In a sixth aspect of the second embodiment, R1a is -CF3 and R1b is -CF3. The values for the remaining variables are as described in the first ment, or any aspect thereof, or the second embodiment, or first through fifth aspects thereof A third embodiment of the invention is a compound of structural formula III: /N \ NNR N" R2 F30 (In), or a pharmaceutically acceptable salt thereof, wherein: Rb is selected from -C(O)OH, ~C(O)NH2, -C(O)-N(R7)-N(R5)(R6), —C(O)~N(R7)—N(R7)-C(O)-R4 and -C(O)-N(R7)-N(R7)—S(O)1.2-R4; wherein: R4 is selected from eN(H)(C3-C6 cycloalkyl), -N(C1-C4 (C3~C6 cycloalkyl), -C1—C6 alkyl, -(C0-C4 alkylene)~carbocyclyl, 4 alkylene)-heterocyclyl, -(C0-C4 alkylene)—aryl, and -(C0-C4 ne)~heteroaryl; R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C2—C4 alkenyl, C2-C4 alkynyl, carbocyclyl, aryl, cyclyl and heteroaryl; or R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl; and each R7 is independently hydrogen or C1—C4 alkyl; and R2 is an optionally substituted C5-C15 heteroaryl, n: unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and aryl is optionally and independently substituted.

Alternative values for the variables in structural formula III are as described in the first embodiment, or any aspect thereof WO 05389 In a first aspect of the third ment, Rb is -C(O)OH; or -C(O)NH2; or -C(O)-NH-NH(R6), and R6 is an optionally substituted heteroaryl; or NH—NH—C(O)-R4 or -C(O)—NH—NH-S(O)1_2-R4, and R4 is ed from optionally substituted —N(H)(C3-C6 cycloalkyl), —N(C1-C4 alkyl)(C3-C6 cycloalkyl), -C1-C6 alkyl, {Co-C4 alkylene)-heterocyclyl and —(C0-C4 alkylene)—heteroaryl. The values for the remaining les are as described in the first embodiment, or any aspect thereof, or the third embodiment.

In a second aspect of the third embodiment, Rb is -C(O)NH2. The values for the remaining variables are as described in the first embodiment, or any aspect f, or the third embodiment, or first aspect thereof.

In a third aspect of the third embodiment, R2 is an optionally substituted 5—6- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The values for the remaining variables are as described in the first embodiment, or any aspect thereof, or the third embodiment, or first or second aspect thereof.

In a fourth aspect of the third embodiment, R2 is an optionally substituted 5- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The values for the remaining variables are as described in the first embodiment, or any aspect thereof, or the third embodiment, or first through third aspects thereof.

In a fifth aspect of the third embodiment, R2 is an optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl. The values for the remaining variables are as described in the first embodiment, or any aspect thereof, or the third embodiment, or first through fourth aspects f.

In a sixth aspect of the third embodiment, R2 is an optionally substituted 6- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The values for the remaining variables are as described in the first ment, or any aspect thereof, or the third embodiment, or first through fifth aspects thereof.

In a seventh aspect of the third ment, R2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, zinyl or triazinyl. The values for the remaining variables are as described in the first embodiment, or any aspect thereof, or the third embodiment, or first through sixth aspects thereof.

In an eighth aspect of the third embodiment, R2 is optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, C1—C4 thioalkoxy, hydroxyl, amino, C1-C4 alkylamino, C1-C4 dialkylamino, sulfliydryl or cyano. The values for the remaining variables are as described in the first embodiment, or any aspect thereof, or the third embodiment, or first h seventh aspects thereof.

In a ninth aspect of the third embodiment, R2 is optionally substituted with halogen, C1-C4 alkyl or C1-C4 alkoxy. The values for the ing variables are as described in the first embodiment, or any aspect thereof, or the third embodiment, or first through eighth aspects thereof.

In a tenth aspect of the third embodiment, Rb is -C(O)OH; or -C(O)NH2; or -C(O)-NH-NH(R6), and R6 is an optionally substituted C5-C6 heteroaryl; or -C(O)-NH-NH-C(O)-R4 or -C(O)-NH—NH—S(O)1-2—R4, and R4 is selected from optionally tuted —N(H)(C3—C6 cycloalkyl), —N(C1—C4 alkyl)(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0- C4 alkylene)—(C3—C7)heterocyclyl and —(C0-C4 alkylene)-(C5-C6)heteroaryl. The values for the remaining variables are as described in the first embodiment, or any aspect thereof, or the third embodiment, or first h ninth aspects thereof.

In an eleventh aspect of the third embodiment, R2 is optionally tuted with 1, 2 or 3 substituents independently selected from halogen, C1—C4 alkyl, l-Cll alkyl, C1-C4 alkoxy, C1-C4 koxy, hydroxyl, amino, C1—C4 alkylamino, C1-C4 dialkylamino, sulfliydryl, cyano, C6 aryl a.nd C5—C6 heteroaryl. Values for the variables are as described in the first embodiment, or any aspect thereof, or the third embodiment, or the first h tenth aspects thereof.

In a h aspect of the third embodiment, R2 is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C1—C4 alkyl, —CF3, amino and cyano. Values for the variables are as described in the first embodiment, or any aspect thereof, or the third embodiment, or the first through eleventh s f.

A fourth ment of the invention is a compound represented by structural formula IV: _ 18 _ F3C O Q—X’lN\ VL/ N NH2 F30 (IV), or a pharmaceutically acceptable salt thereof, wherein R2 is selected from optionally substituted heteroaryl and optionally substituted aryl.

In a first aspect of the fourth ment, R2 is optionally substituted C5—C15 heteroaryl.

In a second aspect of the fourth embodiment, R2 is an ally substituted 5—6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group ting of nitrogen, oxygen and sulfiir.

In a third aspect of the fourth embodiment, R2 is an optionally substituted 5— membered heteroaryl having 1, 2 or 3 heteroatoms ndently selected from the group consisting of nitrogen, oxygen and sulfur.

In a fourth aspect of the fourth embodiment, R2 is an optionally substituted pyrrolyl, furanyl, thiophenyl, lyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl.

In a fifth aspect of the fourth embodiment, R2 is an optionally substituted 6— membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group ting of nitrogen, oxygen and sulfur.

In a sixth aspect of the fourth embodiment, R2 is an optionally substituted nyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl.

In a seventh aspect of the fourth embodiment, R2 is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1—C4 alkyl, halo-Cl—C4 alkyl, C1—C4 alkoxy, C1-C4 thioalkoxy, hydroxyl, amino, C1—C4 alkylamino, C1—C4 dialkylamino, sulfliydryl, cyano, C6 aryl and C5-C6 aryl. Values and alternative values for R2 are as described in the first through third embodiments, or any aspect thereof, or the fourth embodiment, or the first through sixth aspects thereof.

In an eighth aspect of the fourth embodiment, R2 is optionally tuted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C1—C4 alkyl, —CF3, amino and cyano. Values and alternative values for R2 are as described in the first through third _19_ embodiments, or any aspect thereof, or the fourth embodiment, or the first h seventh aspects thereof.

Exemplary compounds are set forth in Table A and Table 1.

Table A.

Structure E isomer 2 isomer 2014/043479 Structure | E isomer 2 isomer WO 05389 Structure E isomer 2 isomer WO 05389 Structure E isomer 2 isomer F30 / \N F30 N _ F30 F30 F30 F30 CF3 CF3 o y o y :0 o o N—N N—N 0 _ DI-N F30 IN» \ O HOD/(M) \ O HOD/kw O>__ CF3 CF3 CFg o 0 FM OH OH __ N' / \ \ OH I "/2 I)!" / N, F30 F30 A2 3/ I (2 0 3/ F30 F3 F3 F3 0 o NH2 NH2 ’ / \ / \ I ’ F30 / a F30 / —.;/ F30 F3 F3 F3 WO 05389 Structure E isomer 2 isomer N’ / \ «9"‘ OH F30 If r "R o F V o o N’ / \ N’ /\ # F30 Hf / F30 If r "RV o F F F3 F3 ___‘:3—______ 0 o NH2 NH2 / \ N’ / \ N, / \ # ’ f ’ f F30 # F30 / NH2 0— ’ o F30 "/2 0— F3 F3 0 o / O OH OH / , OH N N, ’ \ 0 F30 F30 / I K? 0 F3 F3 F3 0 / o NHZ / , NH N 2 ' \ 0 / l '8 0 F30 F30 F30 WO 05389 Structure Eisomer Zisome—_%/N‘N/ N—N N—N ’ N—Nfié; F30 /) ,N\ F30 /N/) F30 ’N) HO NI—I2 / \ N’ F30 ’ h? NI—I2 F30 ’ "/2 \Z N) 0 F3 F3 A:N/ \‘N NI—I2 N, NH2 F30 ‘Z )0 I A? F3; I} F30 / \ F NI—I2 N, , N, NH2 F30? F30 I /) I 30 N F3C F3 F3 NI—I2 _ F HOV ) / \ F30 I N) F3 F3 F30 I 4; F30 I N) NI—I2 F3 F3 2014/043479 Structure E isomer 2 isomer | -26— ure E isomer Zisomer _ Cl F30 I /) / \N F30 N _ F3 F3 _ F F30 I /) / \ N —_ F30 F3 F3 F30 I /) F30 F3 F3 N.—"*ZHMH F30 IN) / \ CF3 F30 F3 F3 ac I Q / \ CN Ffi WO 05389 Structure Eisomer Z isomer Fgc I N) / F30 / \ F3 .._ F3 F30 I (2 F3 F3 Structure E isomer 2 isomer F3C / __ F30 / N.— L[Cl /N‘N\ \N \ F30 1,) /\ /N\N\ N; N — 2! 0 NH2 0 F3 01 F3 NH2 F F F30 /N' __ F F30 /N F3 NHz V — A0 F3 NH2 |_______________ F3 Compounds and Definitions Compounds of this invention include those described generally above, and are further illustrated by the s, subclasses, and species disclosed . As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the ic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are bed in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March’s Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB. and March, J ., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

Unless specified otherwise within this specification, the nomenclature used in this specification lly follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is orated by reference herein for its exemplary chemical structure names and rules on naming chemical ures. ally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 509/September 2001, Advanced try Development, Inc., Toronto, Canada.

Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as dual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.

The term "aliphatic" or atic group," as used herein, s a monovalent hydrocarbon radical that is straight—chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and fused polycyclic). An aliphatic group can be saturated or can contain one or more units of unsaturation, but is not aromatic. Unless otherwise specified, aliphatic groups contain 1—12 carbon atoms. However, in some embodiments, an aliphatic group contains 1—6 or 2—8 carbon atoms. In some embodiments, aliphatic groups contain 14 carbon atoms and, in yet other embodiments, aliphatic groups contain 1—3 carbon atoms.

Suitable tic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term "alky ," as used herein, unless otherwise indicated, means straight or branched saturated monovalent hydrocarbon radicals, typically C1—C12, preferably C1—C6. As such, "C1-C6 alkyl" means a straight or ed saturated monovalent hydrocarbon l having from one to six carbon atoms (e.g., 1, 2, 3, 4, 5 or 6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and l.

The term "alkoxy," as used herein, means an "alkyl—O—" group, wherein alkyl is defined above. Examples of alkoxy include methoxy and ethoxy.

As used herein, the term yl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 12 carbon atoms and having at least one — carbon double bond. Alkenyl groups may be ally substituted with one or more substituents. The term yl" encompasses radicals having carbon—carbon double bonds in the "cis" and " or, alternatively, the "E" and "Z" configurations. If an alkenyl group includes more than one carbon—carbon double bond, each carbon—carbon double bond is independently a cis or trans double bond, or a mixture thereof.

As used herein, the term "alkynyl" means a ted straight chain or branched non—cyclic hydrocarbon having from 2 to 12 carbon atoms and having at least one carbon- carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

As used herein, the term "alkylene" refers to an alkyl group having from 2 to 12 carbon atoms and two points of attachment to the rest of the compound. Non—limiting examples of alkylene groups include methylene (—CH2-), ethylene (-‘CHZCHz-L n-propylene (-CHZCHZCH2-), isopropylene (—CHZCH(CH3)-), and the like. Alkylene groups may be optionally substituted with one or more substituents.

The term "amino," as used herein, refers to a chemical moiety having the formula -N(R)2, wherein each R is independently selected from hydrogen and C1-C4 alkyl.

] The term "aryl," alone or in combination, as used herein, means a carbocyclic aromatic system containing one or more rings, which may be attached together in a pendent manner or may be fused. In particular embodiments, aryl is one, two or three rings. In one aspect, the aryl has six to twelve ring atoms. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, yl, thryl, anthryl and acenaphthyl. An aryl group can be optionally substituted as defined and bed herein.

The terms "cycloaliphatic," "carbocyclyl," "carbocyclo," and "carbocyclic," used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from 3 to 12 members, wherein the aliphatic ring system is optionally substituted as defined and described herein.

Cycloaliphatic groups include, without limitation, cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and cycloalkenyl, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclooctadienyl. The terms "cycloaliphatic," cycly ," "carbocyclo," and "carbocyclic" also include aliphatic rings that are fused to one or more aromatic or matic rings, such as decahydronaphthyl, ydronaphthyl, decalin, or bicyclo[2.2.2]octane.

The term "cycloalkyl", as used , means saturated cyclic hydrocarbons, i.e. compounds where all ring atoms are s. es of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some ments, cycloalkyl can optionally be substituted with one or more substituents selected from -OH, -SH, n, amino, nitro, cyano, C1-C12 alkyl, C2—C12 alkenyl or C2-C12 alkynyl group, C1-C12 alkoxy, C1—C12 haloalkyl, and C1-C12 haloalkoxy.

The term "halo" or "halogen" as used herein means halogen and includes, for e, and without being limited o, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.

The term "haloalkyl", as used herein, includes an alkyl tuted with one or more F, Cl, Br, or I, wherein alkyl is defined above.

The term "heteroaryl", as used herein, refers to an aromatic group containing one or more heteroatoms (e. g., one or more heteroatoms independently selected from O, S and N). A heteroaryl group can be monocyclic or polycyclic, e. g. a monocyclic heteroaryl ring fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups. The heteroaryl groups of this invention can also e ring systems substituted with one or more oxo moieties. In one aspect, heteroaryl has five to fifteen ring atoms and, preferably, 5 or 6 ring atoms. Examples of heteroaryl groups include, but are not d to, pyridinyl, zinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, nolinyl, l, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, azinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, oisoquinolyl, tetrahydroisoquinolyl, benzofiiryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl. The foregoing heteroaryl groups may be C—attached or N—attached (where such is possible). For instance, a group derived from e may be —l—yl (N-attached) or pyrrol—3-yl (C-attached).

"Heterocyclyl" means a cyclic 3-12 membered saturated or unsaturated aliphatic ring containing 1, 2, 3, 4 or 5 heteroatoms (e.g., one or more heteroatoms independently selected from O, S and N). When one heteroatom is S, it can be optionally mono— or di—oxygenated (i.e. —S(O)— or —S(O)2-). The heterocyclyl can be monocyclic or polycyclic, in which case the rings can be attached together in a pendent manner or can be filSCd or spiro.

In one aspect, a heterocyclyl is a three— to seven-membered ring system. Exemplary heterocyclyls include, for example, and without being d o, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.

"Hydroxyl" means -OH.

] "Oxo" means =0. lkoxy" means -S-alkyl, wherein alkyl is defined as above. [001 10] It is tood that substituents and substitution patterns on the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily sized by techniques known in the art, as well as those methods set forth below. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted group" can have a suitable substituent at each substitutable position of the group and, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Alternatively, an "optionally substituted group" can be unsubstitued.

Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically le compounds. If a substituent is itself substituted with more than one group, it is tood that these multiple groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure results.

The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the es sed .

Suitable monovalent substituents on a substitutable carbon atom of an nally substituted group" are independently halogen; —(CH2)MR°; —(CH2)0_4OR°; -O(CH2)0.4R°, —O—(CH2)0_4C(O)OR°; —(CH2)MCH(OR°)2; —(CH2)MSR°; —(CH2)MPh, which may be substituted with R°; —(CH2)040(CH2)0_1Ph which may be tuted with R0; Ph, which may be substituted with R°; —(CH2)040(CH2)(H—pyridyl which may be substituted with IR"; —N02; —CN; —N3; MN(R°)2; —(CH2)MN(R°)C(O)R°; —N(R°)C{S)R°; -(CH2)o4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; —(CH2)04N(R°)C(O)OR°; -N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(O)NR°2; —N(R°)N{R°)C(O)OR°; -(CH2)o4C(O)R°; —C(S)R°; 0-4C(O)OR°; ~(CH2)MC(O)SR°; —(CH2)MC(O)OSiR°3; —(CH2)0_40C(O)R°; —OC{O)(CH2)04SR—, SC(S)SR°; —(CH2)MSC(O)R°; —(CH2)MC(O)NR°2; ~C(S)NR°2; —C(S)SR°; —SC(S)SR°, —(CH2)MOC(O)NR°2; —C{O)N(OR°)R°; (O)R°; 'C(O)CH2C(O)R°; —CCNOR°)R°;'(CH2)MSSR°; -(CH2)043(O)2R°; ‘(CH2)O—4S(O)ZOROQ -(CH2)04OS(0)2R°; —S(0)2NR°2; -(CH2)04S(0)R°; -N(R°)S(0)2NR°2; ~N(R°)S(0)2R°; -N(OR°)R°; -CCNH)NR°2; —P(O)2R°; °2; -OP(O)R°2; —OP(O)(OR°)2; SiR°3; —(C1_4 straight or branched alkylene)O—N(R°)2; or —(C14 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, CM aliphatic, —CH2Ph, —O(CH2)0_1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5—6—membered saturated, partially unsaturated, or aryl ring having 04 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3—12—membered ted, partially unsaturated, or aryl monocyclic or bicyclic ring having 04 heteroatoms independently selected from en, oxygen, and sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° er with their intervening atoms), are independently halogen, -(CH2)0_2R', —(haloR°), —(CH2)0_2OH, ~(CH2)HOR', —(CH2)0_2CH(OR')2; -O(haloR°), —CN, ~N3, ~(CH2)0-2C(O)R°, —(CH2)OW2C(O)OH, 0_2C(O)OR°, —(CH2)0_ 2SR°, ~(CH2)0_2SH, —(CH2)0_2NH2, —(CH2)HNHR', —(CH2)0w2NR'2, —N02, —SiR°3, —OSiR°3, —C(O)SR°, —(C14 straight or branched alkylene)C(O)OR', or —S SR' wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from CH aliphatic, ~CH2Ph, )OW1Ph, or a 5—6—membered saturated, partially rated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

Suitable divalent tuents on a saturated carbon atom of an "optionally substituted group" e the following: :0, =8, =NNR*2, =NNHC(O)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*, =N0R*, —0(C(R*2))2,30—, and —S(C(R*2))2w3S—, wherein each independent ence of R* is selected from hydrogen, C1_6 aliphatic which may be substituted as defined below, or an unsubstituted 5—6—membered saturated, partially unsaturated, or aryl ring having 04 heteroatoms independently ed from nitrogen, oxygen, and . le divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: —O(CR*2)2W30—, wherein each independent occurrence of R* is selected from hydrogen, C14 aliphatic which may be substituted as defined below, or an unsubstituted 5~6——membered saturated, partially unsaturated, or aryl ring having 04 heteroatoms independently selected from nitrogen, , and .

Suitable substituents on the aliphatic group of R* include halogen, —R°, —(haloR°), -OH, ~OR°, —O(haloR°), —CN, —C(O)OH, —C(O)OR°, —NH2, «NHR', —NR°2, and —N02, wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C14 tic, —CH2Ph, )0_1Ph, or a 5—6— membered saturated, partially rated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

Suitable substituents on a substitutable nitrogen of an "optionally substituted group" include —Rl, —NRl2, —C(O)Rl, —C(O)ORT, ~C(O)C(O)Rl, —C(O)CH2C(O)RT, — S(O)2Rl, -S(O)2NRl2, ~C(S)NRl2, —C(NH)NRT2, and —N(RT)S(0)2RT; wherein each RT is independently hydrogen, C1_6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5—6—membered saturated, partially unsaturated, or aryl ring haVing 0—4 heteroatoms independently selected from en, oxygen, and sulfur, or, hstanding the definition above, two independent occurrences of RT, taken together with their intervening atom(s) form an unsubstituted 3—12—membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring haVing 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

Suitable substituents on the aliphatic group of RT are independently n, ~R°, -(haloR'), —OH, —OR', —O(haloR'), -CN, —C(O)OH, —C(O)OR', —NH2, —NHR’, ~NR’2, or -N02, wherein each R' is unsubstituted or where preceded by "halo" is tuted only with one or more ns, and is independently C14 tic, —CH2Ph, —O(CH2)(HPh, or a 5—6— membered saturated, partially unsaturated, or aryl ring haVing 0—4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

Preferred tuents on aryl can be selected from the group consisting of —OH, —SH, nitro, halogen, amino, cyano, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1—C12 alkoxy, C1—C1; haloalkyl, C1-C12 haloalkoxy and C1—C12thioalkoxy. Preferred substituents on alkyl, alkylene and heterocyclyl include the preferred substituents on heteroaryl and oxo. In one embodiment, the substituent on an alkyl, alkylene, heterocyclyl or heteroaryl is an amino group haVing the formula -N(R)2, wherein each R is independently selected from en and C1-C4 alkyl.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals t undue toxicity, irritation, ic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For e, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1—19, incorporated herein by reference. Pharmaceutically acceptable salts of the nds of this invention include those derived from suitable inorganic and organic acids and bases.

Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoroacetic acid (2,2,2-trifluoroacetic acid), oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or c acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, g1ycerophosphate, ate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2—hydroxy—ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, thalenesulfonate, nicotinate, nitrate, , oxalate, palmitate, pamoate, pectinate, fate, 3wphenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, te, thiocyanate, p—toluenesulfonate, trifluoroacetate (2,2,2~trifluoroacetate), undecanoate, te salts, and the like.

Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C114a1kyl)4 salts. Representative alkali or ne earth metal salts include sodium, lithium, potassium, calcium, ium, and the like. Further ceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, e, phosphate, nitrate, lower alkyl sulfonate and aryl ate.

] Unless otherwise , structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereoisomers as well as enantiomeric, diastereomeric, and ric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Unless specifically indicated (by a chemical name or other indicator designating double bond geometry, for example), each structural formula used herein is meant to include compounds having a carbon-carbon double bond (6. g., an exocyclic double bond) with a configuration that is cis (or Z), trans (or E), or a mixture of cis and trans. For example, a I — N:X R2 (1), is meant to denote both: Ra Ra ( R1 )"\<:—\>__ , Similarly, F3C F30 fl)! \ CN /N\N \ CN N/ / N N?! / N F30 I F30 | _ \ the follow1ng structural formulas: and \ :3/ >— The configuration of the exocyclic double bond in Compounds 7, 104, 124 and 153 has been established by x-ray crystallography. The Exemplification reflects whether the exocyclic double bond in Compounds 7, 104, 125 and 153 exists in a cis or trans configuration by indicating the configuration of the exocyclic double bond in the chemical name associated with Compounds 7, 104, 124 and 153.

Compound 7 and Compound 104 serve as intermediates in the synthesis of other compounds described in the Exemplification (e. g., nds 115, 123, 124, etc).

Although not wishing to be bound by any particular theory, it is believed (and supported by x-ray crystallography) that the reactions used to orm Compound 7 or Compound 104, for example, into uent compounds (such as Compounds 115, 123 and 124, for example) proceed in a stereospecific fashion. As such, it is possible to assign a configuration to the exocyclic double bonds in many of the compounds described in the Exemplification.

Where possible, the Exemplification reflects whether the exocyclic double bond in a particular compound exists in a cis or trans configuration by indicating the ration of the exocyclic double bond in the al name associated with the compound.

As used herein, "cis" or "cis configuration" refers to a carbon-carbon double bond, typically an lic double bond, that is predominantly cis. In some embodiments, greater than about 85% of compound molecules in a mixture of the compound have a carbon- carbon double bond (6. g., an exocyclic double bond) that is cis. In some ments, greater than about 90%, greater than about 95%, greater than about 98%, greater than about 99%, greater than about 99.5% or greater than about 99.8% of compound molecules in a mixture of the nd have a carbon-carbon double bond (6. g., an exocyclic double bond) that is cis.

As used herein, "trans" or "trans configuration" refers to a carbon-carbon double bond, typically an lic double bond, that is predominantly trans. In some embodiments, greater than about 85% of compound molecules in a mixture of the compound have a carbon- carbon double bond (6. g., an exocyclic double bond) that is cis. In some embodiments, greater than about 90%, greater than about 95%, greater than about 98%, greater than about 99%, greater than about 99.5% or greater than about 99.8% of compound les in a mixture of the compound have a carbon-carbon double bond (6. g., an exocyclic double bond) that is cis.

Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the ce of one or more isotopically enriched atoms. For example, compounds haVing the present structures ing the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

The term "pharmaceutically able salt" means either an acid addition salt or a basic addition salt which is compatible with the ent of patients. -38— In some embodiments, ary inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form le salts include the mono-, di- and boxylic acids. Illustrative of such acids are, for example, acetic, trifluoroacetic acid (2,2,2—trifluoroacetic acid), glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, ic, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. Other armaceutically acceptable salts, e. g., oxalates may be used, for example, in the isolation of compounds described herein for laboratory use, or for subsequent conversion to a ceutically acceptable acid addition salt.

A "pharmaceutically acceptable basic addition salt" is any non-toxic organic or inorganic base addition salt of the acid compounds described herein or any of its intermediates. Illustrative inorganic bases which form le salts include, but are not d thereto, lithium, , potassium, m, magnesium or barium hydroxides.

Illustrative organic bases which form suitable salts e aliphatic, alicyclic or aromatic c amines such as methylamine, trimethyl amine and picoline or ammonia. The ion of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the le is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

Acid addition salts of the compounds described herein are most suitably formed from pharmaceutically acceptable acids, and include, for example, those formed with inorganic acids, e.g., hydrochloric, sulphuric or phosphoric acids and organic acids, e. g., succinic, maleic, acetic, trifluoroacetic or fumaric acid. Other non-pharmaceutically acceptable salts, e. g., oxalates may be used for example in the isolation of compounds described herein for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of compounds of the invention. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one d in the art.

The term "stereoisomers" is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It es mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).

The term "treat" or "treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

As used herein, "promoting wound healing" means treating a subject with a wound and achieving healing, either partially or fully, of the wound. Promoting wound g can mean, e.g., one or more of the ing: promoting epidermal closure; promoting migration of the dermis; promoting dermal closure in the dermis; reducing wound g complications, e. g., hyperplasia of the epidermis and adhesions; ng wound dehiscence; and ing proper scab formation.

The term "therapeutically effective amount" means an amount of the compound which is effective in treating or ing the severity of one or more symptoms of a disorder or condition. In the case of wound healing, a therapeutically ive amount is an amount that promotes healing of a wound.

The term "pharmaceutically acceptable carrier" means a xic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ient in order to permit the formation of a ceutical composition, i.e., a dosage form capable of being administered to a subject. One example of such a carrier is pharmaceutically acceptable oil typically used for parenteral administration. Pharmaceutically acceptable carriers are well known in the art.

When introducing elements disclosed herein, the articles "a", "an", "the", and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "having", "including" are intended to be open-ended and mean that there may be additional elements other than the listed elements.

Uses, Formulation andAdministration Pharmaceutically Acceptable Compositions ing to another embodiment, the invention provides a composition comprising a compound of this ion or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, nt, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit CRMl, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. The term "patien ", as used herein, means an animal. In some embodiments, the animal is a . In certain embodiments, the patient is a veterinary patient (i.e., a non—human mammal patient). In some embodiments, the patient is a dog. In other embodiments, the patient is a human.

The term "pharmaceutically acceptable carrier, adj uvant, or vehicle" refers to a non-toxic carrier, adj uvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. ceutically able carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum ns, such as human serum albumin, buffer substances such as phosphates, e, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated ble fatty acids, water, salts or electrolytes, such as ine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose— based substances, polyethylene glycol, sodium carboxymethylcellulose, rylates, waxes, polyethylene—polyoxypropylene-block polymers, polyethylene glycol and wool fat. itions of the present invention may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by tion spray, topically, rectally, nasally, buccally, vaginally or via an ted reservoir. In some ~ embodiments, provided compounds or compositions are administrable intravenously and/or intraperitoneally.

The term "parenteral" as used herein includes subcutaneous, intravenous, uscular, intraocular, intravitreal, intra—articular, intra—synovial, intrasternal, intrathecal, intrahepatic, intraperitoneal intralesional and intracranial ion or infusion techniques.

Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated ing to techniques WO 05389 known in the art using suitable sing or wetting agents and suspending agents. The sterile inj ectable preparation may also be a e inj ectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol, Among the acceptable vehicles and solvents that may be ed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a t or suspending medium.

Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also lly added, For oral administration in a capsule form, usefiil diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a provided oral formulation is formulated for immediate release or sustained/delayed release.

In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. A provided compound can also be in micro- encapsulated form, Alternatively, pharmaceutically able itions of this invention may be administered in the form of suppositories for rectal administration. Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, ing es of the eye, the skin, or the lower intestinal tract. Suitable l formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal s may also be used.

For lmic use, provided pharmaceutically acceptable itions may be formulated as micronized suspensions or in an ointment such as petrolaturn.

Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation.

In some embodiments, pharmaceutically able compositions of this invention are formulated for intra—peritoneal administration.

The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. In one embodiment, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be stered to a patient receiving these itions. In another embodiment, the dosage is from about 0.5 to about 100 mg/kg of body weight, or n 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the ements of the particular drug. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day.

It should also be understood that a c dosage and ent regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general , sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.

Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the ms, to a level at which the improved condition is retained when the symptoms have been alleviated to the d level. ts may, however, require ittent ent on a long-term basis upon any recurrence of disease symptoms Uses of Compounds and Pharmaceutically Acceptable Compositions Compounds and compositions described herein are generally useful for the inhibition of CRMl and are therefore useful for treating one or more ers associated with ty of CRMl. Thus, in certain embodiments, the present invention provides a method for treating a CRMl—mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. The compounds and compositions described herein can also be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of ers, including those described herein below.

The activity of a compound utilized in this invention as an inhibitor of CRMl may be assayed in vitro, in vivo or in a cell line. Detailed ions for assaying a compound utilized in this ion as an inhibitor of CRMl are set forth in the Examples below.

As used herein, the term "CRMl-mediated" disorder or condition, as used herein, means any disease or other deleterious ion in which CRMl is known to play a role.

Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which CRMl is known to play a role. In some embodiments, the present invention provides methods of treating a disease associated with sion or activity of p53, p73, p21, pRB, p27, IKB, NFKB, c-Abl, FOXO proteins, COX- 2, or an HDAC ne deacetylases) in a t comprising administering to the patient a therapeutically effective amount of a compound described herein. In another embodiment, the present invention relates to a method of treating or lessening the severity of a disease or condition selected fiom a proliferative disorder (e.g., cancer), an inflammatory disorder, an autoimmune disorder, a viral infection, an ophthalmological disorder or a neurodegenerative disorder wherein said method comprises administering to a t in need thereof a compound or composition according to the present invention. In a more specific embodiment, the present invention relates to a method of treating or lessening the severity of cancer. Specific examples of the above disorders are set forth in detail below. s treatable by the compounds of this invention include, but are not limited to, hematologic malignancies (leukemias, lymphomas, myelomas including le myeloma, myelodysplastic and myeloproliferative mes) and solid tumors (carcinomas such as prostate, breast, lung, colon, atic, renal, ovarian as well as soft tissue and osteosarcomas, and stromal tumors). Breast cancer (BC) can include basal-like breast cancer (BLBC), triple negative breast cancer (TNBC) and breast cancer that is both BLBC and TNBC. In addition, breast cancer can include invasive or vasive ductal or r carcinoma, tubular, medullary, us, papillary, cribriform carcinoma of the breast, male breast cancer, recurrent or metastatic breast cancer, phyllodes tumor of the breast and Paget’s disease of the nipple.

Inflammatory ers treatable by the compounds of this invention include, but are not limited to, multiple sclerosis, rheumatoid arthritis, degenerative joint disease, systemic lupus, ic sclerosis, vasculitis syndromes (small, medium and large vessel), sclerosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative s, gastritis, sepsis, psoriasis and other dermatological inflammatory disorders (such as eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, and dermatosis with acute inflammatory components, pemphigus, pemphigoid, allergic dermatitis), and urticarial syndromes.

Viral diseases treatable by the compounds of this invention include, but are not limited to, acute febrile pharyngitis, pharyngoconj unctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV-l infection (e.g., gingivo stomatitis in children, tonsillitis and pharyngitis in , conjunctivitis), latent HSV-l infection (e.g., herpes labialis and cold sores), primary HSV-2 infection, latent HSV—2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion e, Kaposi’s sarcoma, entric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfectious encephalomyelitis, Mumps, hyperplastic lial s (e.g., , flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, influenza-like syndrome, severe bronchiolitis with pneumonia, German measles, congenital rubella, Varicella, and herpes . Viral diseases treatable by the compounds of this invention also include chronic viral ions, including hepatitis B and hepatitis C.

Exemplary ophthalmology disorders include, but are not limited to, r edema (diabetic and nondiabetic macular edema), aged d macular degeneration wet and dry forms, aged disciform macular degeneration, cystoid macular edema, palpebral edema, retina edema, diabetic retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, , l vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epitheliitis, conjunctivitis, is, scleritis, episcleritis, optic neuritis, retrobulbar optic is, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic nummular keratitis, ophthalmic disease associated with hypoxia or ischemia, retinopathy of prematurity, proliferative diabetic retinopathy, polypoidal dal vasculopathy, retinal angiomatous proliferation, retinal artery occlusion, retinal vein ion, Coats' disease, familial exudative vitreoretinopathy, pulseless disease (Takayasu's disease), Eales disease, antiphospholipid antibody syndrome, leukemic retinopathy, blood hyperviscosity syndrome, macroglobulinemia, interferon— associated retinopathy, hypertensive retinopathy, radiation pathy, corneal epithelial stem cell ncy or cataract.

Neurodegenerative diseases ble by a compound of a I include, but are not limited to, Parkinson’s, Alzheimer’s, and Huntington’s, and Amyotrophic l sclerosis (ALS/Lou Gehrig’s Disease).

Compounds and itions described herein may also be used to treat disorders of abnormal tissue growth and fibrosis including dilative cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, polycystic kidney disorder (PKD) and other renal disorders.

Compounds and compositions described herein may also be used to treat disorders related to food intake such as obesity and hyperphagia.

In another embodiment, a compound or composition described herein may be used to treat or prevent allergies and respiratory disorders, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive ary e (COPD).

In some embodiments, the disorder or condition associated with CRMl activity is muscular dystrophy, arthritis, for example, rthritis and rheumatoid arthritis, ankylosing spondilitis, traumatic brain injury, spinal cord injury, sepsis, rheumatic disease, cancer atherosclerosis, type 1 diabetes, type 2 diabetes, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth ation, hypercholesterolemia, heart disease, chronic heart e, ischemia/reperfusion, stroke, cerebral aneurysm, angina pectoris, ary disease, cystic fibrosis, acid—induced lung injury, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, Sjogren’s syndrome, hyaline membrane e, kidney disease, glomerular disease, lic liver e, gut diseases, peritoneal endometriosis, skin diseases, nasal sinusitis, mesothelioma, anhidrotic ecodermal dysplasia—ID, behcet’s disease, incontinentia pigmenti, tuberculosis, asthma, crohn’s disease, colitis, ocular allergy, icitis, s disease, pancreatitis, onitis, triosis, inflammatory bowel disease, inflammatory lung disease, -induced diseases, sleep apnea, AIDS, HIV-1, autoimmune diseases, antiphospholipid syndrome, lupus, lupus nephritis, familial mediterranean fever, hereditary ic fever syndrome, psychosocial stress es, neuropathological diseases, al amyloidotic polyneuropathy, inflammatory neuropathy, parkinson’s disease, multiple sclerosis, alzheimer’s disease, amyotropic lateral sclerosis, huntington’s disease, cataracts, or hearing loss.

In other embodiments, the disorder or condition associated With CRMl activity is head injury, uveitis, inflammatory pain, allergen induced asthma, non-allergen induced asthma, glomerular nephritis, ulcerative s, necrotizing enterocolitis, mmunoglobulinemia D with recurrent fever , TNF receptor associated periodic syndrome (TRAPS), rin-associated periodic syndromes, Muckle-Wells syndrome (urticaria ss amyloidosis),familial cold urticaria, al onset multisystem inflammatory disease (NOMID), periodic fever, aphthous stomatitis, pharyngitis and is (PFAPA syndrome), Blau syndrome, pyogenic sterile arthritis, pyoderma gangrenosum,acne (PAPA), ency of the interleukin— l——receptor antagonist (DIRA), subarachnoid hemorrhage, polycystic kidney disease, transplant, organ transplant, tissue transplant, myelodysplastic syndrome, irritant-induced inflammation, plant irritant—induced inflammation, poison ivy/ urushiol oil—induced inflammation, al irritant—induced inflammation, bee sting-induced inflammation, insect bite-induced inflammation, sunburn, burns, dermatitis, endotoxemia, lung , acute respiratory distress syndrome, alcoholic hepatitis, or kidney injury caused by parasitic infections.

In further aspects, the present ion provides a use of a compound described herein for the manufacture of a medicament for the treatment of a disease associated with expression or activity of p53, p73, p21, pRB, p27, IKB, NFKB, c—Abl, FOXO proteins, COX— 2 or an HDAC in a subject. In some embodiments, the present invention provides a use of a compound described herein in the manufacture of a medicament for the treatment of any of cancer and/or neoplastic disorders, angiogenesis, mune disorders, inflammatory disorders and/or diseases, epigenetics, hormonal disorders and/or diseases, viral diseases, neurodegenerative disorders and/or diseases, wounds, and ophthalmologic ers.

In some embodiments, the present invention provides a method for inhibiting CRMl in a biological sample sing contacting the biological sample with, or administering to the t, a ceutically acceptable salt of a compound of the invention, or pharmaceutically acceptable composition f Neoplastic Disorders A compound or composition described herein can be used to treat a neoplastic disorder. A "neoplastic disorder" is a disease or disorder characterized by cells that have the capacity for autonomous growth or replication, e. g., an abnormal state or ion characterized by proliferative cell growth. Exemplary neoplastic disorders include: carcinoma, sarcoma, metastatic disorders, e. g., tumors arising from prostate, brain, bone, colon, lung, breast, ovarian, and liver origin, poietic neoplastic disorders, e. g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders, and metastatic tumors. Prevalent cancers include: breast, prostate, colon, lung, liver, and pancreatic cancers.

Treatment with the compound can be in an amount effective to rate at least one symptom of the neoplastic disorder, e. g., reduced cell proliferation, reduced tumor mass, etc.

The sed methods are useful in the prevention and ent of cancer, including for example, solid , soft tissue tumors, and metastases thereof, as well as in familial cancer syndromes such as Li Fraumeni Syndrome, Familial Breast-Ovarian Cancer (BRCAl or BRAC2 mutations) Syndromes, and others. The sed methods are also useful in treating non-solid cancers. Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, id, gastrointestinal (e. g., colon), and genitourinary (e.g,, renal, urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, liver cancer, non—small cell carcinoma of the lung, and cancer of the small intestine.

] Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AID S—Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; ytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder , Childhood; Bone Cancer, arcoma/Malignant Fibrous Histiocytoma; Brain Stem , Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, ood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual y and alamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; oma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood s; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal , Childhood; Cutaneous T—CeIl Lymphoma; trial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; geal Cancer, ood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, lntraocular Melanoma; Eye , Retinoblastoma; Gallbladder Cancer; c (Stomach) Cancer; c (Stomach) , Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; ional Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin’s Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual y Glioma, Childhood; lntraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non—Small Cell; Lung Cancer, Small Cell; Lymphoblastic ia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS— Related; Lymphoma, Central s System (Primary); Lymphoma, Cutaneous T—Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin’s During Pregnancy; Lymphoma, Non—Hodgkin's, Adult; ma, Non- Hodgkin's, Childhood; 2014/043479 Lymphoma, Non~Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; ma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and sal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, ood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous cytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; romocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non~Hodgkin's Lymphoma; Primary Central s System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell y) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; myosarcoma, Childhood; Salivary Gland ; ry Gland Cancer, Childhood; Sarcoma, Ewing’s Family of ; a, Kaposi's; a (Osteosarcoma)/Ma1ignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, ood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; h (Gastric) ; Stomach (Gastric) Cancer, Childhood; entorial Primitive Neuroectodermal Tumors, Childhood; T- Cell ma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown y Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual y and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macroglobulinemia; and Wilms’ Tumor.

Further exemplary cancers include diffuse large B-cell ma (DLBCL) and mantle cell ma (MCL). Yet further exemplary cancers e endocervical cancer, B— cell ALL, T—cell ALL, B- or T-cell lymphoma, mast cell cancer, glioblastoma, lastoma, follicular lymphoma and Richter’s syndrome.

Exemplary sarcomas e fibrosarcoma, alveolar soft part sarcoma (ASPS), liposarcoma, leiomyosarcoma, chondrosarcoma, synovial sarcoma, chordoma, spindle cell sarcoma, histiocytoma, rhabdomyosarcoma, Ewing’s sarcoma, neuroectodermal sarcoma, phyllodes/osteogenic sarcoma and chondroblastic osteosarcoma. ases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein. ation therapies In some embodiments, a compound described herein is administered together with an additional "second" therapeutic agent or treatment. The choice of second therapeutic agent may be made from any agent that is lly used in a monotherapy to treat the indicated e or condition. As used , the term "administered together" and related terms refers to the simultaneous or sequential administration of eutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent aneously or tially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a ceutically acceptable carrier, adjuvant, or vehicle.

In one embodiment of the invention, where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized.

Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this ion. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single ition.

Cancer Combination Therapies ] In some embodiments, a nd described herein is administered er with an additional cancer treatment. Exemplary additional cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, kinase inhibitors, immunotherapy, and hormonal therapy, etic therapy, proteosome inhibitors, and anti- angiogenic therapies. Examples of each of these treatments are provided below. As used , the term "combination, 5, CCcombined," and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For e, a compound of the present invention can be administered with another therapeutic agent aneously or sequentially in separate unit dosage forms or together in a single unit dosage form. ingly, the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of both a compound of the invention and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a nd of the invention can be administered.

Chemotherapy In some embodiments, a compound described herein is administered with a chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy" usually refers to cytotoxic drugs which affect y dividing cells in general, in contrast with targeted therapy. herapy drugs interfere with cell division in various possible ways, e.g., with the duplication ofDNA or the separation of newly formed chromosomes. Most forms of herapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.

Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e,g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl ates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others). ary agents include bicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, Bendamustin, cin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, bine, Clofarabine, taspase, Cyclophosphamide, Cytarabine, azine, omycin, Daunorubicin, Decitabine, lcine, Docetaxel, bicin, Efaproxiral, Elesclomol, trucin, abine, Epirubicin, Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil (SFU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, yurea, Idarubicin, Ifosfamide, ecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, mal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, ocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, stine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfin, Tegafur—uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, rnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.

Because some drugs work better together than alone, two or more drugs are often given at the same time. Often, two or more chemotherapy agents are used as combination chemotherapy. In some embodiments, the chemotherapy agents (including combination chemotherapy) can be used in combination with a compound described herein.

Targeted therapy Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.

Prominent examples are the ne kinase tors such as Axitinib, Bosutinib, Cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an dy which specifically binds to a protein on the surface of the cancer cells. Examples include the anti—HERZ/neu antibody trastuzumab (Herceptin®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies. Other exemplary antibodies include Cetuximab, mumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. ary fusion proteins include Aflibercept and Denileukin diftitox. In some embodiments, the targeted y can be used in combination with a compound bed herein, e.g., Gleevec (Vignari and Wang 2001).

Targeted y can also involve small peptides as "homing devices" which can bind to cell surface ors or affected extracellular matrix surrounding the tumor.

Radionuclides which are attached to these peptides (e. g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An e of such therapy includes BEXXAR®.

Angiogenesis nds and methods described herein may be used to treat or prevent a e or disorder ated with angiogenesis. Diseases associated with angiogenesis include cancer, cardiovascular disease and macular ration.

Angiogenesis is the logical process ing the grth of new blood vessels from pre-existing vessels. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in granulation tissue. However, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one.

Angiogenesis may be a target for combating diseases characterized by either poor vascularisation or abnormal vasculature. ation of specific compounds that may inhibit or induce the creation of new blood vessels in the body may help combat such diseases. The presence of blood vessels where there should be none may affect the mechanical properties of a tissue, increasing the likelihood of failure. The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions. Several diseases, such as ischemic chronic wounds, are the result of failure or insufficient blood vessel formation and may be treated by a local expansion of blood s, thus bringing new nutrients to the site, facilitating repair. Other diseases, such as age-related macular degeneration, may be created by a local ion of blood vessels, interfering with normal physiological processes.

Vascular endothelial growth factor (VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network.

Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment in vascular injuries. In vitro studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because, in the presence of this growth factor, plated endothelial cells will proliferate and e, eventually forming tube structures resembling capillaries.

Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (6. g, VEGF). Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some chers t supply required nutrients, allowing for tumor expansion.

Angiogenesis represents an ent eutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital , namely the production of new collateral vessels to overcome the ischemic insult.

] Overexpression of VEGF causes increased permeability in blood vessels in on to ating enesis. In wet macular degeneration, VEGF causes eration of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina, causing loss of vision.

Anti—angiogenic y can include kinase inhibitors targeting vascular endothelial growth factor (VEGF) such as sunitinib, sorafenib, or monoclonal antibodies or or "decoys" to VEGF or VEGF receptor including bevacizumab or VEGF—Trap, or thalidomide or its analogs (lenalidomide, pomalidomide), or agents targeting non-VEGF WO 05389 angiogenic targets such as fibroblast growth factor (FGF), angiopoietins, or angiostatin or endostatin.

Epigenetics Compounds and methods described herein may be used to treat or prevent a disease or disorder associated with epigenetics. etics is the study of heritable changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence. One example of etic changes in eukaryotic biology is the process of cellular differentiation. During morphogenesis, stem cells become the various cell lines of the embryo which in turn become fully differentiated cells. In other words, a single fertilized egg cell changes into the many cell types including neurons, muscle cells, epithelium, blood vessels etc. as it continues to divide. It does so by activating some genes while inhibiting others.

Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic changes are inherited from one generation to the next. c epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome vation, position effect, reprogramming, transvection, maternal effects, the ss of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.

Exemplary es associated with epigenetics include ATR-syndrome, e X—syndrome, ICF syndrome, Angelman’s syndrome, -Wills syndrome, BWS, Rett syndrome, oc—thalassaemia, cancer, leukemia, Rubinstein—Taybi syndrome and Coffin-Lowry syndrome.

The first human disease to be linked to epigenetics was cancer. Researchers found that diseased tissue from patients with colorectal cancer had less DNA methylation than normal tissue from the same patients. e methylated genes are typically turned off, loss of DNA methylation can cause abnormally high gene activation by ng the arrangement of chromatin. On the other hand, too much methylation can undo the work of protective tumor suppressor genes.

DNA methylation occurs at CpG sites, and a majority of CpG cytosines are methylated in mammals. However, there are stretches ofDNA near promoter regions that WO 05389 ~56- have higher concentrations of CpG sites (known as CpG islands) that are free of methylation in normal cells. These CpG s become excessively methylated in cancer cells, y causing genes that should not be silenced to turn off. This abnormality is the trademark epigenetic change that occurs in tumors and happens early in the development of cancer. ethylation of CpG islands can cause tumors by shutting off tumor-suppressor genes.

In fact, these types of changes may be more common in human cancer than DNA ce mutations.

Furthermore, although epigenetic changes do not alter the sequence of DNA, they can cause mutations. About half of the genes that cause familial or inherited forms of cancer are turned off by methylation. Most of these genes ly suppress tumor formation and help repair DNA, including O6-methylguanine—DNA methyltransferase (MGMT), MLHl cyclin—dependent kinase inhibitor 2B (CDKN2B), and RASSF1A. For example, hypermethylation of the promoter ofMGMT causes the number of G—to-A mutations to increase.

Hypermethylation can also lead to instability of microsatellites, which are repeated sequences of DNA. atellites are common in normal individuals, and they usually consist of repeats of the dinucleotide CA. Too much methylation of the promoter of the DNA repair gene MLH] can make a microsatellite unstable and lengthen or shorten it.

Microsatellite instability has been linked to many cancers, including colorectal, endometrial, ovarian, and gastric cancers.

Fragile X syndrome is the most frequently inherited mental lity, particularly in males. Both sexes can be affected by this condition, but e males only have one X chromosome, one fragile X will impact them more severely. Indeed, fragile X syndrome occurs in approximately 1 in 4,000 males and l in 8,000 females. People with this me have severe intellectual disabilities, d verbal pment, and "autistic-like" behavior.

Fragile X syndrome gets its name from the way the part of the X chromosome that contains the gene abnormality looks under a microscope; it usually appears as if it is hanging by a thread and easily breakable. The syndrome is caused by an abnormality in the FMR] (fragile X mental retardation l) gene. People who do not have e X syndrome have 6 to 50 repeats of the trinucleotide CGG in their FMR] gene. However, individuals with over 200 repeats have a full mutation, and they usually show symptoms of the syndrome. Too many CGGs cause the CpG islands at the promoter region of the FMR] gene to become WO 05389 methylated; normally, they are not. This methylation turns the gene off, ng the FMRJ gene from producing an important protein called fragile X mental retardation protein. Loss of this specific n causes fragile X syndrome. Although a lot of ion has been given to the CGG expansion mutation as the cause of fragile X, the epigenetic change associated with FMRJ methylation is the real syndrome culprit.

Fragile X syndrome is not the only er associated with mental retardation that involves epigenetic changes. Other such conditions include Rubenstein—Taybi, Coffin— Lowry, Prader-Willi, Angelman, Beckwith-Wiedemann, ATR—X, and Rett syndromes.

Epigenetic therapies include inhibitors of enzymes controlling epigenetic modifications, cally DNA methyltransferases and histone deacetylases, which have shown promising anti-tumorigenic s for some malignancies, as well as antisense oligonucleotides and siRNA.

Immunotherapy ] In some embodiments, a compound described herein is administered with an immunotherapy. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, te cancer e Provenge, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients.

Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the s immune cells will often attack the tumor in a graft-versus- tumor effect. In some embodiments, the immunotherapy agents can be used in combination with a compound described herein.

Hormonal therapy In some embodiments, a compound described herein is administered with a hormonal therapy. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone—sensitive tumors include certain types of breast and prostate cancers, as well as certain types of leukemia which d to certain retinoids/retinoic acids. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of e agonists, such as WO 05389 progestogens may be therapeutically beneficial. In some embodiments, the hormonal therapy agents can be used in combination with a compound described .

Hormonal therapy agents include the administration of hormone ts or hormone nists and include retinoids/retinoic acid, compounds that t estrogen or testosterone, as well as administration of progestogens. ation andAutoimmune Disease The compounds and methods described herein may be used to treat or prevent a disease or disorder associated with inflammation, particularly in humans and other s.

A compound described herein may be administered prior to the onset of, at, or after the initiation of inflammation. When used lactically, the compounds are preferably provided in advance of any inflammatory response or symptom. Administration of the compounds can prevent or attenuate atory responses or symptoms. Exemplary inflammatory conditions include, for example, multiple sclerosis, rheumatoid arthritis, psoriatic tis, degenerative joint disease, spondouloarthropathies, other seronegative inflammatory arthridities, polymyalgia rheumatica, s vasculidities (e.g., giant cell arteritis, ANCA+ vasculitis), gouty arthritis, systemic lupus erythematosus, juvenile arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e. g., insulin dependent diabetes mellitus or juvenile onset diabetes), menstrual cramps, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, esophagitis, atitis, peritonitis, Alzheimer‘s disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, atis (acute or chronic), le organ injury syndrome (e.g., secondary to septicemia or trauma), myocardial infarction, atherosclerosis, stroke, reperfusion injury (e. g., due to cardiopulmonary bypass or kidney dialysis), acute glomerulonephritis, thermal injury (i.e., sunburn), necrotizing colitis, granulocyte transfusion associated syndrome, and/or Sjogren’s me. Exemplary inflammatory conditions of the skin include, for e, eczema, atopic dermatitis, contact dermatitis, urticaria, schleroderma, psoriasis, and dermatosis with acute inflammatory components.

In another embodiment, a compound or method described herein may be used to treat or prevent allergies and respiratory conditions, including asthma, bronchitis, pulmonary fibrosis, ic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD). The compounds B and hepatitis C. may be used to treat chronic hepatitis infection, ing hepatitis WO 05389 Additionally, a compound or method described herein may be used to treat autoimmune diseases and/or inflammation associated with autoimmune diseases, such as organ-tissue autoimmune diseases (e.g., Raynaud’s syndrome), scleroderma, enia graVis, transplant rejection, xin shock, sepsis, sis, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, s, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular e (also known as autoimmune polyglandular syndrome), and Grave’s disease.

In a particular embodiment, the compounds described herein can be used to treat multiple sis.

Combination therapy In certain embodiments, a compound described herein may be administered alone or in combination With other compounds useful for treating or preventing inflammation.

Exemplary anti-inflammatory agents include, for example, steroids (e.g., Cortisol, cortisone, fludrocortisone, prednisone, 6[alpha]-methylprednisone, inolone, betamethasone or dexamethasone), nonsteroidal antiinflammatory drugs (NSAIDS (e. g, n, acetaminophen,tolmetin, fen, mefenamic acid, cam, nabumetone, rofecoxib, celecoxib, etodolac or nimesulide). In another embodiment, the other therapeutic agent is an otic (e.g., vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, rifampinmetronidazole, doxycycline or streptomycin). In another embodiment, the other therapeutic agent is a PDE4 inhibitor (6. g, roflumilast or rolipram). In another embodiment, the other therapeutic agent is an antihistamine (e.g. , cyclizine, hydroxyzine, promethazine or diphenhydramine). In another embodiment, the other eutic agent is an anti-malarial (e. g., artemisinin, artemether, artsunate, chloroquine phosphate, ine hydrochloride, doxycycline hyclate, proguanil hydrochloride, atovaquone or halofantrine). In one embodiment, the other compound is drotrecogin alfa.

Further examples of anti-inflammatory agents e, for e, aceclofenac, acemetacin, e—acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alclofenac, alclometasone, alfentanil, algestone, allylprodine, alminoprofen, aloxiprin, alphaprodine, um bis(acetylsalicylate), amcinonide, c, aminochlorthenoxazin, 3-amino-4— hydroxybutyric acid, 2-amino picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antrafenine, apazone, beclomethasone, bendazac, —60- benorylate, benoxaprofen, benzpiperylon, benzydarnine, benzylrnorphine, bermoprofen, betarnethasone, ethasone— 17-Valerate, amide, [alpha]-bisabolol, nac, p- brornoacetanilide, 5-brornosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid, bucolorne, budesonide, bufexarnac, burnadizon, buprenorphine, butacetin, butibufen, hanol, carbarnazepine, carbiphene, caiprofen, carsalarn, chlorobutanol, prednisone, chlorthenoxazin, choline salicylate, phen, cinmetacin, cirarnadol, clidanac, clobetasol, clocortolone, clornetacin, clonitazene, clonixin, clopirac, cloprednol, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cortisone, cortivazol, croproparnide, crotetharnide, cyclazocine, deflazacort, dehydrotestosterone, desornorphine, desonide, desoxirnetasone, dexarnethasone, dexarnethasone—21- isonicotinate, dexoxadrol, rnoramide, dextropropoxyphene, deoxycorticosterone, dezocine, diamprornide, diamorphone, enac, difenarnizole, irarnide, diflorasone, diflucortolone, diflunisal, difluprednate, dihydrocodeine, dihydrocodeinone enol acetate, dihydrornorphine, dihydroxyaluminurn acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiarnbutene, dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol, droxicam, emorfazone, enfenarnic acid, enoxolone, epirizole, eptazocine, late, ethenzarnide, ethoheptazine, ethoxazene, ethylrnethylthiambutene, ethylrnorphine, etodolac, etofenarnate, etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, one, floctafenine, fluazacort, flucloronide, flufenarnic acid, flumethasone, lide, flunixin, flunoxaprofen, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, tin butyl, fluocoitolone, fluoresone, fluorornetholone, fluperolone, flupirtine, fluprednidene, fluprednisolone, fluproquazone, renolide, flurbiprofen, fluticasone, formocortal, fosfosal, ic acid, glafenine, glucarnetacin, glycol salicylate, guaiazulene, halcinonide, halobetasol, halornetasone, haloprednone, heroin, hydrocodone, hydro ate, hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, hydrocortisone hemisuccinate, hydrocortisone 21 ate, hydrocortisone cypionate, hydrornorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxarn, imidazole salicylate, indomethacin, ofen, isofezolac, isoflupredone, isoflupredone acetate, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobernidone, ketoprofen, ketorolac, p- lactophenetide, lefetarnine, levallorphan, levorphanol, levophenacyl-rnorphan, lofentanil, lonazolac, lornoxicarn, loxoprofen, lysine salicylate, mazipredone, meclofenarnic acid, medrysone, mefenarnic acid, carn, meperidine, meprednisone, meptazinol, WO 05389 —61- mesalamine, metazocine, methadone, methotrimeprazine, prednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone suleptnate, inic acid, metofoline, metopon, mofebutazone, mofezolac, mometasone, morazone, ne, morphine hydrochloride, morphine sulfate, line salicylate, myrophine, nabumetone, nalbuphine, nalorphine, l-naphthyl salicylate, naproxen, narceine, m, nicomorphine, nifenazone, niflumic acid, lide, 5'—nitro-2’- propoxyacetanilide,norlevorphanol, normethadone, normorphine, anone, olsalazine, opium, oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paramethasone, paranyline, parsalmide, pentazocine, perisoxal, etin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenomorphan, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, amidol, profen, piminodine, pipebuzone, piperylone, pirazolac, amide, piroxicam, pirprofen, pranoprofen, prednicarbate, solone, prednisone, prednival, prednylidene, proglumetacin, tazine, promedol, propacetamol, properidine, propiram, propoxyphene, propyphenazone, proquazone, protizinic acid, proxazole, ramifenazone, remifentanil, rimazolium metilsulfate, salacetamide, salicin, salicylamide, salicylamide o- acetic acid, salicylic acid, salicylsulfuric acid, salsalate, salverine, simetride, sufentanil, sulfasalazine, ac, superoxide dismutase, suprofen, quibuzone, umate, tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine, tinoridine, tixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone, triamcinolone acetonide, tropesin, viminol, xenbucin, Ximoprofen, zaltoprofen and zomepirac.

In one ment, a compound described herein may be administered with a selective COX-2 inhibitor for treating or preventing inflammation. Exemplary selective COX—2 inhibitors include, for example, deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, and lumiracoxib.

In some embodiments, a provided compound is administered in combination with an anthracycline or a Topo ll inhibitor. In certain embodiments, a provided compound is administered in combination with Doxorubicin (Dox). In certain embodiments, a provided compound is administered in combination with bortezomib (and more broadly including carfilzomib). It was singly found that a ed compound in combination with Dox or bortezomib resulted in a synergystic effect (i.e., more than additive).

Viral infections WO 05389 —62- Compounds and methods described herein may be used to treat or prevent a disease or disorder associated with a viral infection, particularly in humans and other mammals. A compound described herein may be administered prior to the onset of, at, or after the initiation of viral infection. When used prophylactically, the compounds are preferably provided in advance of any viral infection or symptom thereof. ary viral diseases include acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular oma, primary HSV—l infection (6. g, gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-l infection (6. g., herpes labialis and cold sores), primary HSV—2 infection, latent HSV—2 infection, c meningitis, ious mononucleosis, Cytomegalic inclusion disease, Kaposi’s sarcoma, multicentric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfectious encephalomyelitis, Mumps, hyperplastic epithelial lesions (6. g, common, flat, plantar and ital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, yelitis, Rabies, influenza—like syndrome, severe iolitis with nia, German s, ital rubella, Varicella, and herpes zoster.

Exemplary viral influenza A s include HlNl, H3N2, H5N1, H7N3, H7N9.

A compound described herein can also be used to treat or prevent influenza B.

Exemplary viral pathogens include Adenovirus, Coxsackievirus, Dengue virus, Encephalitis Virus, Epstein-Barr virus, Hepatitis A virus, tis B virus, Hepatitis C virus, Herpes simplex virus type 1, Herpes simplex virus type 2, cytomegalovirus, Human herpesvirus type 8, Human immunodeficiency virus, Influenza virus, measles virus, Mumps virus, Human papillomavirus, Parainfluenza virus, Poliovirus, Rabies virus, Respiratory syncytial virus, Rubella virus, Varicella—zoster virus, West Nile virus, Dungee, and Yellow fever virus. Viral pathogens may also include s that cause resistant viral infections, Antiviral drugs are a class of medications used specifically for treating viral infections. ral action generally falls into one of three mechanisms: interference with the ability of a virus to infiltrate a target cell (6. g, amantadine, rimantadine and pleconaril), inhibition of the synthesis of virus (6. g., nucleoside ues, e. g, acyclovir and zidovudine (AZT), and inhibition of the release of virus (6. g., zanamivir and oseltamivir). -63— Ophthalmology Compounds and methods described herein may be used to treat or prevent an ophthamology disorder. Exemplary ophthamology disorders e macular edema (diabetic and nondiabetic macular edema), age related macular degeneration wet and dry forms, aged disciform macular degeneration, cystoid macular edema, palpebral edema, retina edema, diabetic retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment litis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal ment, corneal ulcer, conjunctival ulcer, chronic nummular keratitis, ophthalmic disease associated with hypoxia or ischemia, pathy of prematurity, proliferative diabetic retinopathy, polypoidal choroidal opathy, retinal angiomatous proliferation, retinal artery occlusion, retinal vein ion, Coats’ disease, familial exudative vitreoretinopathy, pulseless e (Takayasu’s disease), Eales e, antiphospholipid antibody syndrome, leukemic retinopathy, blood hyperviscosity syndrome, lobulinemia, eron- associated pathy, hypertensive retinopathy, radiation retinopathy, corneal epithelial stem cell deficiency and cataract.

Other ophthalmology disorders treatable using the compounds and methods described herein include proliferative vitreoretinopathy and chronic retinal detachment.

Inflammatory eye diseases are also treatable using the compounds and methods described herein.

Neurodegenerative e Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including son’s, Alzheimer’s, and Huntington’s occur as a result of egenerative processes.

As research progresses, many similarities appear which relate these es to one r on a sub-cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many es simultaneously. There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death.

Alzheimer’s disease is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss s in gross atrophy of the WO 05389 —64- affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.

Huntington’s disease causes astrogliosis and loss of medium spiny s. Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices. The striatum’s subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder. Exemplary treatments for Huntington’s disease include tetrabenazine, eptics, benzodiazepines, dine, remacemide, valproic acid, selective serotonin reuptake inhibitors (SSRIs), mirtazapine and antipsychotics.

The mechanism by which the brain cells in son’s are lost may consist of an abnormal lation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha~synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies. The latest research on pathogenesis of disease has shown that the death of dopaminergic s by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles ~ the asmic reticulum (ER) and the Golgi apparatus. n proteins like Rabl may reverse this defect caused by alpha-synuclein in animal models.

Exemplary Parkinson’s disease therapies e levodopa, dopamine agonists such as include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride, dopa decarboxylate inhibitors, MAO—B inhibitors such as selegilene and rasagilene, anticholinergics and amantadine.

] Amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease) is a disease in which motor neurons are selectively targeted for degeneration. ary ALS therapies include riluzole, baclofen, diazepam, yphenidyl and amitriptyline.

Other exemplary neurodegenerative therapeutics include nse oligonucleotides and stem cells.

Wound Healing Wounds are a type of condition characterized by cell or tissue damage. Wound healing is a dynamic pathway that lly leads to restoration of tissue integrity and function. The wound healing process consists of three overlapping phases. The first phase is —65- an inflammatory phase, which is characterized by homeostasis, platelet aggregation and degranulation. Platelets as the first response, release le growth factors to recruit immune cells, epithelial cells, and endothelial cells. The inflammatory phase typically occurs over days 0—5. The second stage of wound healing is the proliferative phase during which macrophages and granulocytes invade the wound. Infiltrating fibroblasts begin to produce collagen. The principle characteristics of this phase are epithelialization, angio genesis, granulation tissue formation and collagen production. The proliferative phase typically occurs over days 3-14. The third phase is the remodeling phase where matrix formation occurs. The fibroblasts, epithelial cells, and endothelial cells continue to produce collagen and collagenase as well as matrix metalloproteases (MMPs) for remodeling. en crosslinking takes place and the wound undergoes contraction. The remodeling phase typically occurs from day 7 to one year.

Compounds and compositions described herein can be used for promoting wound healing (e. g, ing or accelerating wound closure and/or wound healing, mitigating scar fibrosis of the tissue of and/or around the wound, inhibiting apoptosis of cells surrounding or proximate to the wound). Thus, in certain embodiments, the present invention provides a method for ing wound healing in a subject, comprising administering to the subject a therapeutically effective amount of a compound (e. g., a CRMl inhibitor), or ceutically able salt or composition thereof. The method need not achieve te healing or e of the wound; it is sufficient for the method to promote any degree of wound closure. In this t, the method can be employed alone or as an adjunct to other methods for healing wounded .

The compounds and compositions described herein can be used to treat wounds during the inflammatory (or early) phase, during the proliferative (or middle) wound healing phase, and/or during the remodeling (or late) wound healing phase.

In some embodiments, the subject in need of wound healing is a human or an animal, for example, a dog, a cat, a horse, a pig, or a rodent, such as a mouse.

In some embodiments, the compounds and compositions described herein useful for wound healing are administered topically, for example, ate to the wound site, or systemically.

More cally, a therapeutically effective amount of a compound or composition described herein can be administered (optionally in combination with other -66— ) to the wound site by coating the wound or applying a bandage, packing material, stitches, etc., that are coated or d with the compound or composition described herein.

As such, the compounds and compositions bed herein can be formulated for topical administration to treat surface . Topical formulations include those for delivery via the mouth l) and to the skin such that a layer of skin (i.e., the epidermis, dermis, and/or subcutaneous layer) is contacted with the compound or composition described herein.

Topical delivery systems may be used to administer topical formulations of the compounds and compositions described herein.

Alternatively, the compounds and compositions described herein can be administered at or near the wound site by, for example, injection of a solution, injection of an extended release formulation, or introduction of a radable implant comprising the compound or composition described herein.

The compounds and compositions described herein can be used to treat acute wounds or chronic wounds. A c wound results when the normal reparative process is interrupted. Chronic wounds can develop from acute injuries as a result of unrecognized persistent infections or inadequate primary treatment. In most cases however, chronic lesions are the end stage of progressive tissue breakdown owing to venous, arterial, or lic vascular disease, re sores, radiation damage, or tumors.

In chronic wounds, healing does not occur for a variety of reasons, including improper circulation in diabetic ulcers, significant necrosis, such as in burns, and infections.

In these chronic wounds, viability or the recovery phase is often the rate-limiting step. The cells are no longer viable and, thus, initial recovery phase is prolonged by unfavorable wound bed nment.

] Chronic wounds include, but are not limited to the following: chronic ischemic skin lesions; scleroderma ulcers; arterial ulcers; diabetic foot ; pressure ulcers; venous ulcers; non—healing lower extremity wounds; ulcers due to atory conditions; and/or long—standing wounds. Other examples of chronic wounds include chronic ulcers, diabetic wounds, wounds caused by diabetic neuropathy, venous insufficiencies, and arterial insufficiencies, and pressure wounds and cold and warm burns. Yet other examples of chronic wounds include chronic ulcers, ic wounds, wounds caused by diabetic neuropathy, venous insufficiencies, arterial insufficiencies, and pressure wounds. -67— Acute wounds include, but are not d to, post-surgical wounds, lacerations, hoids and fissures.

] In a particular embodiment, the compounds and compositions described herein can be used for diabetic wound healing or accelerating healing of leg and foot ulcers secondary to diabetes or ischemia in a subject.

In one ment, the wound is a surface wound. In another embodiment, the wound is a surgical wound (e. g., abdominal or gastrointestinal surgical wound). In a further embodiment, the wound is a burn. In yet another embodiment, the wound is the result of ion exposure.

The compounds and compositions described herein can also be used for ic wound healing, gastrointestinal wound healing, or healing of an adhesion due, for example, to an operation.

The compounds and compositions described herein can also be used to heal wounds that are secondary to r disease. For example, in inflammatory skin diseases, such as sis and dermatitis, there are numerous incidents of skin lesions that are secondary to the disease, and are caused by deep cracking of the skin, or scratching of the skin. The compounds and compositions described herein can be used to heal wounds that are secondary to these diseases, for example, inflammatory skin diseases, such as psoriasis and dermatitis.

In a further embodiment, the wound is an internal wound. In a specific , the internal wound is a chronic wound. In another specific aspect, the wound is a vascular wound. In yet another specific aspect, the internal wound is an ulcer. Examples of internal wounds include, but are not limited to, fistulas and internal wounds associated with cosmetic surgery, internal indications, Crohn’s disease, ulcerative colitis, al surgical sutures and skeletal fixation. Other examples of internal wounds include, but are not limited to, fistulas and internal wounds associated with ic surgery, al indications, internal surgical s and al fixation.

Examples of wounds include, but are not limited to, abrasions, ons, blowing wounds (i.e., open pneumothorax), burn wounds, contusions, gunshot wounds, incised wounds, open wounds, penetrating wounds, perforating , puncture wounds, seton wounds, stab wounds, surgical wounds, subcutaneous wounds, diabetic lesions, or tangential wounds. Additional examples of wounds that can be treated by the compounds and —68— compositions described herein include acute conditions or wounds, such as thermal burns, chemical burns, radiation burns, burns caused by excess exposure to ultraviolet radiation (e. g., sunburn); damage to bodily tissues, such as the um as a result of labor and irth; injuries sustained during medical procedures, such as episiotomies; trauma- induced injuries including cuts, incisions, excoriations; es sustained from accidents; post-surgical injuries, as well as chronic conditions, such as pressure sores, bedsores, conditions related to diabetes and poor circulation, and all types of acne. In addition, the wound can include dermatitis, such as impetigo, intertrigo, folliculitis and eczema, wounds following dental surgery; periodontal disease; wounds following ; and tumor- associated wounds. Yet other examples of wounds include animal bites, arterial disease, insect stings and bites, bone infections, compromised skin/muscle grafts, gangrene, skin tears or lacerations, skin aging, surgical incisions, including slow or non—healing surgical , intracerebral hemorrhage, sm, dermal asthenia, and post-operation infections.

In preferred embodiments, the wound is selected from the group consisting of a burn wound, an incised wound, an open wound, a surgical or post surgical wound, a diabetic lesion, a thermal burn, a chemical burn, a radiation burn, a pressure sore, a bedsore, and a condition related to diabetes or poor circulation. In more preferred embodiments, the wound is ed from the group ting of an incised wound, an open wound, a surgical or post al wound, a diabetic lesion, a pressure sore, a bedsore, and a condition or wound related to diabetes or poor circulation.

In some embodiments, the wound is selected from the group ting of a non- radiation burn wound, an incised wound, an open wound, a surgical or post surgical wound, a diabetic lesion, a thermal burn, a chemical burn, a pressure sore, a bedsore, and a condition related to diabetes or poor circulation. In some embodiments, the wound is selected from the group ting of an incised wound, an open wound, a surgical or post surgical wound, a ic lesion, a pressure sore, a bedsore, and a condition d to diabetes or poor circulation.

The t disclosure also relates to methods and compositions of reducing scar ion during wound healing in a subject. The compounds and compositions described herein can be administered directly to the wound or to cells proximate the wound at an amount effective to reduce scar formation in and/or around the wound. Thus, in some embodiments, a method of reducing scar formation during wound healing in a subject is 2014/043479 -69— provided, the method comprising administering to the t a therapeutically effective amount of a compound described herein (e. g., a CRMl inhibitor), or a pharmaceutically acceptable salt f.

The wound can include any injury to any portion of the body of a subject.

According to embodiments, methods are provided to ameliorate, reduce, or decrease the formation of scars in a t that has suffered a burn injury. According to preferred embodiments, methods are provided to treat, reduce the ence of, or reduce the probability of developing hypertrophic scars in a subject that has suffered an acute or chronic wound or injury.

Other disorders Compounds and compositions described herein may also be used to treat ers of abnormal tissue growth and fibrosis including dilatiVe cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, and other renal disorders.

Combination ion Therapy Compounds and compositions described herein are useful as radiosensitizers.

Therefore, compounds and itions described herein can be administered in combination with radiation therapy. Radiation therapy is the l use of high-energy radiation (e. g., x-rays, gamma rays, charged particles) to shrink tumors and kill malignant cells, and is lly used as part of cancer treatment. Radiation therapy kills malignant cells by damaging their DNA.

Radiation therapy can be delivered to a patient in several ways. For example, radiation can be red from an external source, such as a machine outside the patient’s body, as in external beam radiation therapy. External beam radiation therapy for the treatment of cancer uses a radiation source that is external to the patient, typically either a radioisotope, such as 60Co, 137Cs, or a high energy x-ray source, such as a linear accelerator.

The external source produces a collimated beam directed into the patient to the tumor site.

External-source radiation therapy avoids some of the ms of internal-source radiation therapy, but it rably and necessarily irradiates a significant volume of non-tumorous or y tissue in the path of the radiation beam along with the tumorous tissue.

The adverse effect of irradiating of healthy tissue can be reduced, while maintaining a given dose of radiation in the us tissue, by projecting the external radiation beam into the patient at a variety of "gantry" angles with the beams converging on the tumor site. The particular volume elements of healthy , along the path of the radiation beam, change, reducing the total dose to each such element of healthy tissue during the entire ent.

The irradiation of healthy tissue also can be reduced by y collimating the radiation beam to the general cross section of the tumor taken dicular to the axis of the radiation beam. us s exist for producing such a circumferential collimation, some of which use multiple sliding shutters which, piecewise, can generate a radio-opaque mask of arbitrary outline.

For administration of al beam radiation, the amount can be at least about 1 Gray (Gy) fractions at least once every other day to a treatment . In a particular embodiment, the radiation is administered in at least about 2 Gray (Gy) fractions at least once per day to a treatment volume. In r particular embodiment, the radiation is administered in at least about 2 Gray (Gy) fractions at least once per day to a treatment volume for five consecutive days per week. In another particular embodiment, radiation is administered in 10 Gy fractions every other day, three times per week to a treatment volume.

In another particular embodiment, a total of at least about 20 Gy is administered to a patient in need thereof. In another particular embodiment, at least about 30 Gy is administered to a patient in need thereof In another particular embodiment, at least about 40 Gy is administered to a patient in need thereof.

Typically, the patient receives external beam therapy four or five times a week. An entire course of treatment usually lasts from one to seven weeks depending on the type of cancer and the goal of treatment. For example, a patient can receive a dose of 2 Gy/day over 30 days.

] Internal radiation therapy is localized radiation therapy, meaning the radiation source is placed at the site of the tumor or affected area. Internal radiation therapy can be delivered by placing a radiation source inside or next to the area requiring treatment. Internal ion therapy is also called therapy. Brachytherapy includes intercavitary treatment and interstitial treatment. In intracavitary treatment, containers that hold radioactive sources are put in or near the tumor. The s are put into the body cavities.

In interstitial treatment, the radioactive sources alone are put into the tumor. These 2014/043479 radioactive sources can stay in the patient permanently. Typically, the radioactive sources are removed from the patient after several days. The radioactive sources are in containers.

There are a number of methods for stration of a harmaceutical agent.

For example, the radiopharmaceutical agent can be administered by targeted ry or by systemic delivery of targeted radioactive conjugates, such as a abeled antibody, a abeled peptide and a liposome delivery system. In one particular embodiment of targeted delivery, the radiolabelled pharmaceutical agent can be a radiolabelled antibody.

See, for example, Ballangrud A. M., et al. Cancer Res., 2001; 61 :2008-2014 and Goldenber, D.M. J. Nucl. Med, 2002; 43(5):693-713, the contents ofwhich are incorporated by reference herein.

In another particular embodiment of targeted delivery, the radiopharmaceutical agent can be administered in the form of liposome delivery systems, such as small unilamellar es, large unilamellar vesicles and multilamellar vesicles. mes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or atidylcholines. See, for example, Emfietzoglou D, elos K, S gouros G. An analytical dosimetry study for the use of radionuclide—liposome conjugates in internal radiotherapy. J Nucl Med 2001; 42:499—504, the contents of which are incorporated by reference herein.

In yet another particular embodiment of targeted delivery, the radiolabeled pharmaceutical agent can be a radiolabeled peptide. See, for example, Weiner RE, Thakur ML. Radiolabeled peptides in the sis and therapy of oncological diseases. Appl Radiat Isot 2002 Nov;57(5):749-63, the contents of which are incorporated by reference herein.

In on to targeted delivery, bracytherapy can be used to r the radiopharmaceutical agent to the target site. Brachytherapy is a technique that puts the radiation sources as close as possible to the tumor site. Often the source is inserted directly into the tumor. The radioactive sources can be in the form of wires, seeds or rods. Generally, cesium, iridium or iodine are used.

Systemic radiation therapy is another type of radiation therapy and involves the use of radioactive substances in the blood. Systemic radiation therapy is a form of targeted therapy. In ic radiation therapy, a patient typically ingests or receives an injection of a radioactive nce, such as radioactive iodine or a ctive substance bound to a monoclonal antibody.

A "radiopharmaceutical agent," as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various es. The radiolabelled pharmaceutical agent, for e, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation . As contemplated herein, the term "radioisotope" includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical ation of the abeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is lly employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non—metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule.

As used herein, a "metallic radioisotope" is any suitable metallic radioisotope useful in a therapeutic or diagnostic procedure in vivo or in vitro. Suitable metallic radioisotopes include, but are not limited to: um-225, Antimony-124, Antimony- 125, Arsenic—74, Barium—103, Barium—140, Beryllium-7, Bismuth-206, Bismuth-207, h212, Bismuth213 Cadmium-1 15m, Calcium-45, Cerium-13 9, Cerium- 141, , Cadmium-109, Cerium—144, Cesium—137, Chromium—51, Cobalt-55, Cobalt-56, Cobalt-57, Cobalt-58, Cobalt-60, Cobalt-64, Copper-60, Copper—62, Copper-64, -67, Erbium-169, Europium-152, Gallium-64, Gallium-67, Gallium-68, Gadolinium153, Gadolinium-157 Gold—195, 99, Hafnium—175, Hafnium—175—1 8 1 Indium-l 10, Indium— , Holmium-166, 111, Iridium-192, Iron 55, 9, n85, Lead-203, Lead—210, Lutetium—177, Manganese-54, y—197, Mercury203, Molybdenum-99, Neodymium-147, Neptunium- 23 7, -63, Niobium95, Osmium-185+191, Palladium-103, Palladium-109, Platinum— 195m, Praseodymium- 143 , Promethium—147, Promethium- 149, Protactinium-23 3, Radium- 226, m-l 86, Rhenium— 1 8 8, Rubidium-86, Ruthenium-97, Ruthenium-103 , Ruthenium-105, Ruthenium—106, Samarium-153, Scandium—44, Scandium—46, Scandium-47, Selenium—75, Silver—110m, Silver-111, Sodium—22, Strontium—85, Strontium—89, Strontium- 90, Sulfur-3 5, Tantalum—182, Technetium-99m, Tellurium—125, Tellurium—132, Thallium- 204, Thorium—228, Thorium—232, Thallium-170, Tin-1 13 , Tin-1 14, Tin-1 17m, Titanium—44, _73_ Tungsten—185, Vanadium—48, Vanadium—49, Ytterbium—l69, Yttrium-86, Yttrium—8 8, Yttrium—90, Yttrium—91, 5, Zirconium-89, and Zirconium-95.

As used herein, a "non-metallic radioisotope" is any suitable nonmetallic radioisotope (non-metallic radioisotope) useful in a eutic or diagnostic procedure in vivo or in vitro. Suitable non—metallic radioisotopes include, but are not limited to: - 131, Iodine-125, Iodine—123, Phosphorus-32, Astatine-211, Fluorine-18, -l 1, Oxygen— , Bromine-76, and Nitrogen-13.

Identifying the most appropriate isotope for herapy requires weighing a y of factors. These include tumor uptake and retention, blood clearance, rate of radiation delivery, half-life and specific activity of the radioisotope, and the feasibility of large—scale production of the radioisotope in an economical fashion. The key point for a therapeutic radiopharmaceutical is to deliver the requisite amount of radiation dose to the tumor cells and to achieve a cytotoxic or tumoricidal effect while not causing unmanageable side-effects.

It is preferred that the physical half-life of the therapeutic radioisotope be similar to the biological half-life of the radiopharmaceutical at the tumor site. For example, if the half-life of the radioisotope is too short, much of the decay will have ed before the radiopharmaceutical has reached maximum /background ratio. On the other hand, too long a half—life could cause ssary radiation dose to normal tissues. Ideally, the radioisotope should have a long enough half-life to attain a minimum dose rate and to irradiate all the cells during the most radiation sensitive phases of the cell cycle. In addition, the ife of a radioisotope has to be long enough to allow adequate time for manufacturing, release, and transportation.

] Other practical considerations in selecting a radioisotope for a given application in tumor therapy are availability and quality. The purity has to be sufficient and reproducible, as trace amounts of impurities can affect the radiolabeling and radiochemical purity of the radiopharmaceutical.

The target receptor sites in tumors are typically limited in number. As such, it is preferred that the radioisotope have high specific activity. The specific activity depends primarily on the production . Trace metal contaminants must be minimized as they often compete with the radioisotope for the chelator and their metal xes compete for receptor binding with the radiolabeled chelated agent.

] The type of radiation that is suitable for use in the methods of the present invention can vary. For example, radiation can be electromagnetic or particulate in nature.

Electromagnetic radiation useful in the practice of this invention es, but is not d to, x-rays and gamma rays. ulate radiation useful in the practice of this invention includes, but is not limited to, electron beams (beta particles), protons beams, neutron beams, alpha particles, and negative pi mesons. The radiation can be delivered using conventional radiological treatment apparatus and methods, and by intraoperative and stereotactic methods.

Additional discussion regarding radiation treatments suitable for use in the ce of this invention can be found throughout Steven A. Leibel et al., ok of ion Oncology (1998) (publ. W. B. Saunders Company), and particularly in Chapters 13 and 14. ion can also be delivered by other methods such as targeted delivery, for example by radioactive "seeds," or by systemic delivery of ed radioactive conjugates. J. Padawer er al., Combined Treatment with Radioestradiol lucanthone in Mouse C3HBA Mammary Adenocarcinoma and with Estradiol lucanthone in an Estrogen Bioassay, Int. J. .

Oncol. Biol. Phys. 7:347-357 (1981). Other radiation delivery methods can be used in the practice of this invention.

For tumor y, both on and B-particle emitters have been investigated. Alpha particles are particularly good cytotoxic agents because they dissipate a large amount of energy within one or two cell diameters. The B~particle emitters have relatively long penetration range (2-12 mm in the tissue) depending on the energy level. The long-range penetration is particularly important for solid tumors that have heterogeneous blood flow and/or receptor expression. The B-particle emitters yield a more homogeneous dose bution even when they are heterogeneously distributed within the target tissue.

In a particular embodiment, therapeutically effective amounts of the compounds and compositions described herein are administered in combination with a therapeutically effective amount of radiation therapy to treat cancer (6. g., lung cancer, such as non-small cell lung cancer). The amount of radiation necessary can be determined by one of skill in the art based on known doses for a particular type of . See, for example, Cancer Medicine 5th ed., Edited by RC. Bast et al., July 2000, BC Decker.

The above disclosure generally describes the present invention. A more complete tanding can be obtained by reference to the following specific es. These es are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render ent. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.

EXEMPLIFICATION Abbreviations aq. Aqueous DMF N,N—Dimethylformamide DMSO . Dimethylsulfoxide eq. equivalent(s) Et Ethyl EtOAc Ethyl acetate g gram h hour(s) HPLC High performance liquid chromatography LCMS Liquid Chromatography Mass Spectrometry Me methyl mg milligram(s) min minute mL milliliters NMM yl morpholine NMR Nuclear magnetic resonance Ph phenyl THF Tetrahydrofuran IR Retention time Throughout the following description of such ses it is to be tood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and ediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting for example, in groups as well as examples of le protecting groups are described, ctive Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley—lnterscience, New York, (1999). It is also to be understood that a transformation of a group or substituent -76— into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by nt incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a le order, will be readily tood to the one skilled in the art of organic synthesis. Examples of transformations are given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions on other suitable transformations are given in "Comprehensive Organic Transformations — A Guide to Functional Group Preparations" R.

C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March, 4th ed. McGraw Hill (1992) or, "Organic Synthesis", Smith, McGraw Hill, (1994). Techniques for purification of ediates and final products include for example, straight and reversed phase chromatography on column or rotating plate, tallization, distillation and liquid-liquid or solid—liquid extraction, which will be readily understood by the one skilled in the art. The definitions of substituents and groups are as in a 1 except where defined differently. The term "room temperature" and "ambient ature" shall mean, unless ise specified, a temperature between 16 and 25 °C.

The term "reflux" shall mean, unless otherwise stated, in reference to an employed t a temperature at or above the boiling point of named solvent.

Example 1. Synthetic Procedures sis of 3-(3-(3, 5-bis (trifluoromethyl) phenyl)-1H-1,2,4-triazolyl)(pyridin—2— yl) acrylonitrile (100): OACN kaigvNH2NH2 H20 / H(OEt3) /N NH—NH2 CH3l /N\N/\{ n CH(OEtg) HN-NH N N/ \ F30 \ CH3COOH Synthesis of 3-eth0xy(pyn'dinyl) acrylonitrile (2): 2—Pyridyl acetonitrile (1) (1.00 g, 8.46 mmol) and triethyl orthoformate (1.25 g, 8.46 mmol) were added to acetic anhydride (1.73 g, 16.93 mol) at room ature. The resulting reaction mixture was heated at 100 °C for 3 h, cooled to room temperature, diluted with water (500 mL), and extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804, and Concentrated under reduced pressure to give 800 mg of crude 3-ethoxy(pyridin—2-y1) acrylonitrile (2), which was used without further purification in the following step. Yield (34%), LCMS: m/z 175.20 , rR= 1.52 min.

Synthesis of 3-hydrazi11yl(pyn'din-2—yl) acrylonitrile (3): 3—Ethoxy(pyridin—2-y1) acrylonitrile (2) (800 mg, 4.59 mmol) and hydrazine hydrate (230 mg, 4.59 mmol) were added to water (8 mL) at room temperature. The reaction e was heated at 80 °C for 1 h, cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (3 X 100 mL). The ed organic layers were washed with brine, dried over anhydrous Na2804, and trated under reduced pressure to give 435 mg of crude 3—hydrazinyl—2—(pyridin—2-y1) acrylonitrile (3), which was used without further ation in the following step. Yield (42%), LCMS: m/z 161.18 [M+H]+, rR = 0.24 min.

Synthesis of methyl 3, triflu0r0methyl)benzimidothioate (5): 3,5—Bis (trifluoromethyl) benzothioamide (4) (15.0 g, 54.91 mmol) and methyl iodide (38.97 g, 274.53 mmol, 17.1 mL) were added to diethyl ether (120 mL) at 0 °C .The reaction mixture was stirred at room temperature for 12 h. The solid product was filtered and dried to give methyl 3,5—bis (trifluoromethyl) benzimidothioate (5). Yield (8 g, 51%), 1H NMR (400 MHz, DMSO-dg) 5 8.51 (s, 1H), 8.44 (s, 2H), 2.72 (s, 3H).

Synthesis of methyl-N'-(2-cyan0—2-(pyridin—2—yl)vinyl)—3,5—bis(trifluoromethyl) idohydrazide (6): Methyl 3, 5—bis (trifluoromethyl) benzimidothioate (5) (300 mg, 1.04 mmol) and azinyl-2—(pyridinyl) acrylonitrile (3) (184 mg, 1.15 mmol) were added to dimethylformamide (1.5 mL) at room temperature. After stirring at room ature for 1 h, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2804 and concentrated under d pressure to give 400 mg of crude N'—(2—cyano-2— (pyridiny1)Vinyl)-3,5—bis(trifluoromethyl) benzimidohydrazide (6) which was used t further purification in the following step. Yield (96%).

Synthesis of 3-(3-(3,5-bis(triflu0r0methyl)phenyl)—1H-1,2,4—triazol-1—yl)(pyridin—2- yl)acrylonitrile (100): N'—(2—cyano(pyridinyl) —3,5—bis (trifluoromethyl) benzimidohydrazide (6) (400 mg, 1.00 mmol) and triethyl orthoformate (148 mg, 1.00 mmol) was added to acetic acid (2 mL) at room temperature. The reaction mixture was heated at 100 °C for 30 min.

After cooling to room temperature, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (2 x 50 mL). The ed organic layers were washed with brine, dried over anhydrous Na2804, concentrated under reduced pressure and purified by silica gel chromatography to afford 3-(3-(3,5—bis (trifluoromethyl) phenyl)—1H—1,2,4—triazol— 1—yl)—2—(pyridin—2—yl) acrylonitrile (100). Yield (100 mg, 24 %). 1H NMR (400 MHZ, DMSO-dg) 5 10.11 (s, 1H), .01 (m, 3H), 8.68—8.67 (m, 1H),'8.47-8.45 (m, 2H), 8.05-8.00 (m, 1H), 7.36-7.33 (m, 1H). LCMS: m/z 410.29 [M+H]+, tR=2.71 min.

Synthesis of (E)—is0pr0pyl 3—(3—(3,5-bis(triflu0r0methyl)phenyl)-1H-1,2,4-triazol-1—yl) (pyridinyl)acrylate (101): General Procedure 1: Suzuki cross-coupling -79_ 2 9H N r / B‘OH ’ N) F3C ____.__.._.\N Pd(PPh3)4, 032003, dioxane,H20 (Z)—lsopropy1 3-(3-(3,5—bis(trifluoromethyl)phenyl)- 1H—1,2,4-triazol—1-yl)—2- crylate (7) (1.0 g, 2.0 mmol), pyridine 3—boronic acid (0.39 g, 3.20 mmol) and a solution of cesium carbonate (1.38 g,4.0 mmol) in water (5 mL) were added to e (20 mL) at room temperature, degassed and purged with N2. Tetrakis(triphenylphosphine) palladium (0) (0.23 g, 0.2 mmol) was added to the reaction mixture and the resulting mixture was degassed, and purged with N2. The reaction mixture was stirred at 50 0C for 12 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl e (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2804 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using (10% EtOAc in hexane) to give (E)-isopropy1 3-(3—(3, 5-bis uoromethyl) phenyl)-1H—1, 2, 4—triazol-1—yl)(pyridinyl) acrylate (101). Yield (0.399 g,40%),1H NMR (400 MHZ, DMSO-dg) 5 9.16 (s, 1H), 8.58 (s, 2H), 8.48 (s, 1H), 8.23 (s, 1H), 8.06 (s, 2H), 7.74 (d, J: 7.2 Hz, 1H), .45 (m, 1H), 5.12-5.06 (m, 1H), 1.28—1.26 (m, 6H). LCMS: m/z 471.37 [M+H]+, tR=2.73 min.

Syntheses of (E)—3-(3-(3,5—bis(trifluoromethyl)phenyl)—1H-1,2,4-triazolyl)—2-(pyridin- 3-yl)acrylonitrile (102), (E)-3—(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazolyl)— 2-(pyridinyl)acrylic acid (103) and (3—(3,5—bis(trifluoromethyl)phenyl)—1H- 1,2,4-triazolyl)—2-(pyridin—3-yl)acrylamide (104): ~80— 0 Q— 0 _ LiOH _ N—N ~—~> N—N F3C // / \N THF,H20 F3C / / / \N N —- N _ F30 101 F30 103 Clio/fi/ NMM,NH3 CN NH2 N—N N—N F30 l/ré/EN POCI3 F30 ,/ / \N N — N .— F3C 102 F30 104 Synthesis of (E)—3—(3—(3,5-bis(trifluoromethyl)phenyl)—1H—1,2,4—triazol—1-yl)(pyridin- 3-yl)acrylic acid (103).

General Procedure 2: Ester Hydrolysis ] Isopropyl (E)—3—(3—(3,5—bis (trifluoromethyl) phenyl)-1H—1,2,4—triazol—1—yl)—2— (pyridin—3-yl) te (101) (1.1 g, 2.3 mmol) was dissolved in a solution of THF: H20 (1:1) (11 mL) and 20 (0.29 g, 7.0 mol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The on mixture was transferred into iced water and neutralized using 3M HCl solution (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined c layers were washed with brine and dried over anhydrous Na2804. The organic layer was concentrated under reduced pressure and the crude product was purified by silica gel chromatography (6% MeOH in CH2C12) to give (E)—3—(3—(3,5— bis(trifluoromethy1)phenyl)-1H—1,2,4-triazol—1—y1)—2-(pyridin—3-y1)acry1ic acid (103). Yield (0.42 g, 42%), 1H NMR (400 MHZ, DMSO-dg) 5 13.33 (s, 1H), 9.12 (s, 1H), .56 (m, 2H), 8.46 (s, 1H), 8.23 (s, 1H), 8.07 (s, 2H), 7.74—7.70 (m, 1H), 7.47—7.43 (m, 1H).

LCMS: m/Z 429,29 [M+H]+, m = 2.17 min.

Synthesis of (E)-3—(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)(pyridin- 3-yl)acrylamide (104).

General Procedure 3: Conversion of carboxylic acid to primary amide (E)—3 -(3 -(3,5—Bis(trifluoromethyl)pheny1)-1H—1,2,4—triazol-1—yl—2-(pyridin—3 —yl) acrylic acid (103) (1 g, 2.3 mmol) was dissolved in THF (10 mL) and cooled to O 0C. To the WO 05389 solution was added isobutyl chloroformate (0.49 g, 3.64mmol), N—methyl morpholine (0.33 g, 3 .26 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and ammonia gas was purged through the filtrate for 15 min at 0 °C.

The reaction mixture was transferred into ice water and compound was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous . The organic layer was concentrated under reduced pressure and the crude product was purified by silica gel chromatography to give 0.370 g of (E)(3-(3,5- bis(trifluoromethyl) phenyl)~1H—1,2,4—triazolyl)(pyridin—3-yl) acrylamide (104). Yield (0.370 g, 37%), 1H NMR (400 MHz, DMSO-dg) 5 8.99 (s, 1H), 8.61-8.59 (m, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 8.09 (s, 2H), 7.71—7.69 (m, 1H), 7.61 (s, 1H), 7.48— 7.45 (m, 1H), 7.23 (s, 1H). LCMS: m/z 428.30 [M+H]+, tR= 2.31 min.

Synthesis of (E)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4—triazolyl)(pyridin- 3-yl)acrylonitrile (102).

General Procedure 4: Conversion of primary amide to nitrile (E)—3-(3—(3,5~Bis(trifluoromethyl)phenyl)—1H—1,2,4~triazol—l~yl)(pyridin—3— yl)acrylamide (104) (260 mg, 0.60 mmol) was dissolved in dimethylformamide (5 mL) and cooled to 0 0C to which was added orus oxychloride (110 mg, 1.21 mmol). The reaction mixture was stirred at 0 °C for 1 h, transferred into iced water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, trated under reduced pressure. The crude product was purified by silica gel chromatography to give (E)—3-(3—(3,5—bis(trifluoromethyl)phenyl)-lH—l,2,4—triazol- 1-yl)—2-(pyridin—3-yl)acrylonitrile Yield (0.08 g, 32%), 1H NMR (400 MHz, DMSO-dg) 9.04 (s, 1H), 8.73 (s, 1H), .67 (m, 1H), 8.59 (s, 1H), 8.28 (s, 1H), 8.13 (s, 2H), 8.00— 7.97 (m, 1H), 7.55-7.52 (m, 1H). LCMS: m/z 410.0 [M+H]+, tR= 2.37 min.

Syntheses of (E)(3-(3,5-bis(trifluor0methyl)phenyl)—1H—1,2,4-triazolyl)-2—(pyridin- 4-yl)acrylonitrile (105), pyl (E)(3-(3,5—bis(triflu0romethyl)phenyl)-1H—1,2,4- triazol—l-yl)—2-(pyridinyl)acrylate (106), (E)—3-(3-(3,5-bis(trifluoromethyl)phenyl)—1H- 1,2,4-triazolyl)(pyridin-4—yl)acrylic acid (107), and (E)(3-(3,5- bis(trifluoromethyl)phenyl)—1H-1,2,4-triazolyl)(pyridin—4-yl)acrylamide (108): O >_ (PH 0 >— O | _ N\ ‘ N~N r N’N LIOH N’N F30 I) ————>F30 I/)/\"'—’F30 /)/\ N Pd(PPh3)4, 052003, N THFv "20 —N N —N dioxane.H20 7 106 107 F30 F30 F30 A NMM,NH3 CN NH2 N~N N—N F30 I )% P0013 F30 / /) / \ N ‘———*— '"N N —-N F30 F30 105 108 Synthesis of isopropyl (E)—3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4—triazolyl)-2— (pyridin-4—yl)acrylate (106): Isopropyl (E)-3~(3-(3,5-bis(trifluoromethyl)phenyl)—lH—l,2,4-triazol~1-yl)—2- (pyridin—4-yl)acrylate (106) was synthesized using General ure 1. Yield (9%), 1H NMR (400 MHz, DMSO~d6) 5 9.13 (s, 1H), 8.63-8.61 (m, 2H), 8.54 (s, 1H), 8.24 (s, 1H), 8.06 (s, 2H), 7.34—7.32 (m, 2H), 5.10-5.06 (m, 1H), 1.27—1.25 (m, 6H). LCMS: m/z 471.5 [M+H]+, 3 min.

Synthesis of (E)—3-(3-(3,5-bis(triflu0romethyl)phenyl)—1H-1,2,4-triazol—1—yl)(pyridin- 4-yl)acrylic acid (107): (E)-3—(3—(3,5-Bis(trifluoromethyl)phenyl)-1H—1,2,4-triazol—1—yl)(pyridin—4— yl)acrylic acid (107) was sized using General Procedure 2. Yield (52%), 1H NMR (400 MHz,DMSO—d6)513.38(s, 1H), 9.12—9.08 (m, 1H), .53 (m, 3H), 8.25-8.22 (m, 1H), 8.10—8.06 (m, 2H), 7.35—7.31 (m, 2H). LCMS: m/z 429.11 [M+H]+, tR=2.01 min.

Synthesis of (E)(3—(3,5—bis(trifluoromethyl)phenyl)-1H—1,2,4-triazol—1-yl)-2—(pyridin- 4-yl)acrylamide (108).

(E)—3-(3-(3,5-Bis(trifluoromethyl)phenyl)—1H-l,2,4-triazol—1-yl)—2—(pyridin-4~ yl)acrylamide (108) was synthesized using General Procedure 3. Yield (33%), 1H NMR (400 MHz, DMSO-dg) 5 8.95 (s, 1H), 8.66—8.62 (m, 2H), .23 (m, 2H), 8.09 (s, 2H), 7.63 (s, 1H), 7.31—7.29 (m, 2H), 7.18 (s, 1H). LCMS: m/z 428.16 [M+H]+, tR=2.10 min.

Synthesis of (E)(3—(3,5-bis(triflu0r0methyl)phenyl)—1H—1,2,4—triazol—1-yl)—2-(pyridin- 4-yl)acrylonitrile (105): (E)—3—(3 ~(3 ,5 —Bis(trifluoromethyl)phenyl)-1H—l,2,4—triazolyl)—2—(pyridin yl)acrylonitrile (105) was synthesized using General Procedure 4. Yield (58%), 1H NMR (400 MHz, DMSO—dg) 6 9.16 (s, 1H), 9.04 (s, 1H), 8.77-8.75 (m, 2H), 8.61 (s, 2H), 8.38 (s, 1H), 7.72-7.70 (m, 2H). LCMS: m/z 410.1 [M+H]+, 4 min.

Synthesis of isopropyl (Z)—3-(3-(3,5-bis(triflu0r0methyl)phenyl)-1H—1,2,4-triazol—1-yl) (thiazol-Z-yl)acrylate (109), (Z)(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazol—l- yl)(thiazolyl)acrylonitrile (110) and (Z)(3-(3,5-bis(triflu0r0methyl)phenyl)—1H— 1,2,4-triazol-l-yl)(thiazolyl)acrylamide (1 11) o 3‘ 0 9‘ E SnBu3 N’N S N’N 8 N-N r .

F30 , /) Fae / /) N’ / LIOH FaC / /) NV N N N TH F H o 3)4,dioxane ’ 2 7 109 8 F3C FaC F30 A NMM, NHa CI 0 CN NH2 N—Nis P0013 N'N S /) I I FaC I N /J <——-—— F30 I /) N /J N DMF N FaC 110 F30 111 Synthesis of isopropyl (Z)-3—(3-(3,5-bis(trifluoromethyl)phenyl)-1H—1,2,4-triazolyl) (thiazolyl)acrylate (109): lsopropyl (Z)-3—(3~(3,5—bis(trifluorornethyl)phenyl)-lH—l,2,4-triazolyl)—2- (thiazolyl)acrylate (109) was synthesized using General Procedure 5, which is bed in detail for the synthesis of (3-(3,5—bis(trifluoromethyl)phenyl)—1H—1,2,4-triazol-l-yl)- N,N—dimethyl—2-(pyridinyl)acrylamide (113). Yield (54%). 1H NMR (400 MHz, DMSO- dg) 5 9.27 (s, 1H), 9.12 (s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 8.22 (s, 2H), 7.88 (s, 1H), .01 (m, 1H), 1.25 (d, J: 6 Hz, 6H). LCMS: m/z 477.18 [M+H]+, IR = 2.94 min.

Synthesis of (Z)(3-(3,5-bis(triflu0r0methyl)phenyl)-1H-1,2,4-triazol-l-yl)—2-(thiazol yl)acrylic acid (8): (Z)-3—(3—(3 ,5~Bis(trifluoromethyl)phenyl)—1H—1,2,4-triazol-l—yl)(thiazol—2- yl)acrylic acid (8) was synthesized using General Procedure 2 and the crude product was used in the next step without purification.

WO 05389 Synthesis of (Z)—3-(3-(3,S—bis(trifluoromethyl)phenyl)—1H-1,2,4—triazol-l—yl)—2—(thiazol—2— yl)acrylamide (111): ] (Z)—3—(3—(3,5—Bis(trifluoromethyl)phenyl)—lH—1,2,4—triazol—1—yl)—2—(thiazol-2— ylamide (111) was synthesized using General Procedure 3. Yield (55%). 1H NMR (400 MHz, DMSO-dg) 5 9.26 (s, 1H), 9.97 (s, 1H), 8.26—8.22 (m, 4H), 7.87 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H). LCMS: m/z 434.21 [M+H]+, 1R = 2.28 min. sis of (Z)-3—(3—(3,5-bis(triflu0romethyl)phenyl)-1H—1,2,4-triazol—1—yl)—2—(thiazol—2— yl)acrylonitrile (110): (3 —(3 ,5—Bis(trifluoromethyl)phenyl)—1H—1,2,4—triazol—l—yl)—2—(thiazol—2—yl) acrylonitrile (110) was synthesized using l Procedure 4. Yield (3 0%). 1H NMR (400 MHz, DMSO-dg) 5 9.36 (s, 1H), 9.36 (s, 1H), 9.09 (s, 1H), 8.53 (s, 1H), 8.42 (s, 2H), 8.35 (s, 1H), 8.30 (s, 1H). LCMS: m/z 416.01 [M+H]+, IR: 2.69 min.

Synthesis of (E)—(3-(3—(3,5—bis(triflu0r0methyl)phenyl)-1H—1,2,4—triazol—1-yl)-N,N— dimethyl(pyridin-3—yl)acrylamide (112): NMM MezNH, THF 112 \ (E)——3—(—3—(3, 5—Bis(trifluoromethyl)phenyl)— 1H—1 2,4—triazol 1—yl)———2(pyridin——3— yl)acrylic acid (103) (0.15 g, 0.35 mmol) was dissolvedin THF (5 mL) at room temperature.

The on mixture was cooled to 0 °C and isobutyl chloroformate (0.067 mL, 0.525 mmol) was added dropwise. 4—methyl morpholine (0.04 mL, 0.52 mmol) was then added. The reaction e was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was filtered and the filtrate was cooled to 0 °C. Dimethylamine (2N in THF, 2 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 15 min, warmed to room temperature, transferred into iced water, and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0—5% MeOH: CHZClz) to obtain (E)—3—(3 —(3 ,5—bis(trifluoromethyl) phenyl)—1H—1,2,4—triazol—1—yl)—N,N—dimethyl—2~(pyridin—3 — yl)acrylamide (112). (Yield: 0.040 g, 25%). 1H NMR (400 MHz, DMSO—d6) 5 8.82 (s, 1H), 8.57 (s, 1H), 8.56 (s, 1H ), 8.23 (s, 1H), 8.21 (s, 2H), 7.80 (d, J: 11.6 Hz, 1H), 7.68 (s, 2014/043479 -85— 1H), 7.45-7.42 (m, 1H), 2.97 (s, 3H), 2.88 (s, 3H). LCMS: m/z 456.61 [M+H]', tR=2.30 min.

Synthesis of (E)-(3-(3-(3,5-bis(triflu0r0methyl)phenyl)—1H-1,2,4-triazol—1-yl)-N,N- dimethyl—2~(pyridinyl)acrylamide (1 13): O o N/ 0 OH N/ \ \ N’N r O N , N N4N / \ Fso\©/I\NI /> C|/U\O/W/ I Bugsn‘QN— I F3C N/> FsC\©/kN/> "N NMM, Me NH, THF Pd(PPhs)4.

CF3 2 CFS 1,4-Dioxane 01:3 14 113 sis of (Z)—3-(3-(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazol—1-yl)br0m0- NJV-dimethylacrylamide (9): ] (Z)(3 -(3 ,5—Bis(trifluorornethyl)phenyl)—1H—1,2,4-triazol-l-yl)—2-brornoacrylic acid (7) (0.5 g, 1.16 mmol) was dissolved in THF (10 mL) at room temperature. The reaction mixture was cooled to 0 °C and isobutyl chloroformate (0.22 mL, 1.74 mmol) was added drop wise. yl morpholine (0.19 mL, 1.74 mmol) was then added to the reaction e and stirred for 5 min. The on mixture was allowed to warm to room temperature, stirred for 30 min and filtered. The filtrate was cooled to 0 °C and dimethylamine (2N in THF, 2 mL) was added dropwise and stirred for 15 min. The reaction mixture was allowed to warm to room temperature, transferred into iced water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2804 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0—5% MeOH: CHzClz) to obtain (Z)-3 -(3 —(3 ,5 -bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)—2-bromo—N,N—dimethyl mide (9). (Yield: 0.2 g, 37%). 1H NMR (400 MHz, DMSO d6) 6 9.41 (s, 1H), 8.70 (s, 1H), 8.57 (s, 2H), 8.32 (s, 1H), 2.97 (s, 3H), 2.88 (s, 3H). LCMS: m/z 457.17 [M+H]', tR = 2.5 5 min.

Synthesis of (E)-(3-(3-(3,5—bis(triflu0r0methyl)phenyl)~1H-1,2,4—triazol—1-yl)-N,N- dimethyl(pyridinyl)acrylamide (1 13): General Procedure 5: Stille Coupling (Z)—3—(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol—1-yl)—2-bromo-N,N— dimethylacrylamide (9) (0.2 g, 0.437 mmol) was dissolved in dry 1,4-dioxane (10 mL) at room temperature and degassed using N2 for 30 min. 4-(tributylstannyl)pyridine (0.19 g, 2014/043479 0.524 mmol) and tetrakis(triphenylphosphine) ium (0) (0.05 g, 0.0437 mmol) were added and the reaction mixture was heated at 90 0C for 2 h and then cooled to room temperature. The on mixture was transferred into iced water and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to give crude compound which was purified by column silica gel chromatography using (0-5% MeOH : CHzClz) to obtain (E)—(3 ~(3 —(3,5-bis(trifluoromethyl)phenyl)-1H—l,2,4-triazolyl)-N, N—dimethyl-2— (pyridinyl)acrylamide (113). (Yield: 0.05 g, 25%). 1H NMR (400 MHz, DMSO-dg) 5 9.02 (s, 1H), 8.67 (d, J: 5.6 Hz, 2H), 8.52 (s, 2H), 8.33 (s, 1H), 8.21 (s, 1H), 7.49 (d, J = 6 Hz, 2H), 3.10 (s, 3H), 2.85 (s, 3H). LCMS: m/z 456.31 [M+H]+, tR = 2.20 min.

Synthesis of (E)-3—(3-(3,S-bis(trifluoromethyl)phenyl)—1H-1,2,4—triazol—1-yl)—2-(1-methyl- 1H—pyrazol—4—yl)acrylamide (114): OH Clio/Y NMM, NH3, THF (E)(3—(3,5-Bis(trifluoromethyl)phenyl)—lH—1,2,4-triazolyl)~2-(1 -methyl-1H- pyrazol—4—yl) acrylamide (114) was synthesized using l procedure 3. (Yield: 0.01 g, 33%). 1H NMR (400 MHz, DMSO-dg) 5 8.79 (s, 1H), 8.45 (s, 2H), 8.28 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 3.84 (s, 3H). LCMS: m/z 431.21 [M+H]+, m = 2.22 min.

Synthesis of isopropyl (E)(3-(3,5-bis(trifluor0methyl)phenyl)-1H-1,2,4—triazolyl) (pyrimidin-S-yl)acrylate (115): General Procedure 6: Suzuki coupling — Method 2 or r F3C FSC ’NJN \B$0 Hd " ,N‘ \ / 4 Pd(PPh3)2Clz / F CH3COOK, F W 3 7 3 115 e,H20 Isopropyl-(E)— 3-(3-(3,5—bis(trifluoromethyl)phenyl)- lH—l ,2,4—triazol—1—yl)—2— bromoacrylate (7) (0.7 g, 1.48 mmol), pyrimidine 5-boronic acid (0.22 g, 1.77 mmol) and a —87- solution of potassium acetate (0.43 g, 4.4 mmol) in water (3.0 mL) were added in dioxane (15 mL) at room temperature, degassed and purged with N2. Bis(triphenylphosphine) palladium (H) dichloride (0.1 g, 0.14 mmol) was added and the on mixture was degassed, and purged with N2. The reaction mixture was stirred at 100 0C for 12 h, diluted with water (150 mL) and ted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous NazSO4 and concentrated under reduced pressure.

The crude product was purified by silica gel chromatography (30% EtOAc in hexane) to give isopropyl—(E)—3 —(3 — (3 , 5 -bis(trifluoromethyl)phenyl)— 1H— 1 ,2,4-triazolyl)(pyrimidin- crylate (115) (Yield: 0.2 g, 20%). 1H NMR (400 MHz, DMSO—d6) 5 9.26 (s, 1H), 9.20 (s, 1H), 8.79 (s, 2H), 8.68 (s, 1H), 8.26 (s, 1H), 8.07 (s, 2H), 5.13—5.07 (m, 1H), 1.27 (d, J: 6 Hz, 6H). LCMS: m/z 472.22 [M+H]+, tR=2.73 min.

Synthesis of isopropyl (E)—3-(3-(3,5-bis uoromethyl) phenyl)-1H-1, 2, 4-triazol—1-yl)- 2—(3,S-dimethylisoxazolyl) acrylate (116): >50 O 0 EH >5 ——O \ \OH ,4 ,_ O Br "N N "N \N/ I > l FEED/k / / ~————-—» F3 \ ,O N Pd(PPh3)ZC|2 CH300OK, Dloxane,H20 C\©/KN CF3 7 CF3 116 Isopropyl (E)-3—(3—(3,5—bis (trifluoromethyl) phenyl)—1H—1, 2, 4-triazolyl)—2-(3, —dimethylisoxazol-4—yl) te (116) was synthesized using General Procedure 6. : 0.2 g, 20 %). 1H NMR (400 MHz, DMSO—d6) 5 9.21 (s, 1H), 8.63 (s, 1H), 8.29 (s, 3H), .10—5.07 (m, 1H), 2.16 (s, 3H), 1.98 (s, 3H), 1.27 (d, J: 6 Hz, 6H). LCMS: m/z 489.22 [M+H]+, 1R: 2.95 min.

Synthesis of (E)(3-(3,S-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazol—1-yl)—2-(3,5- dimethyl isoxazol—4—yl) acrylic acid (117) I /> \ ,0 LiOH.H20 : F30 F30 /> \ ’0 N N —‘—" ’ N N THF.H20 (E)(3-(3,5—Bis (trifluorornethyl) phenyl)—1H—1, 2, 4-triaZ01yl)—2—(3, 5 - dirnethyl isoxazol—4—yl) acrylic acid (117) was synthesized using l Procedure 2.

(Yield: 0.1 g, 50%). 1H NMR (400 MHZ, DMSO—d6) 6 13.37 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 8.29 (s, 3H), 2.15 (s, 3H), 1.98 (s, 3H). LCMS: m/z 447.23 [M+H]+, tR= 2.46 min.

Synthesis of (E)—3-(3-(3,5-bis(trifluoromethyl)phenyl)—1H—1,2,4-triaz01—1-yl)(3,5- dimethyl isoxazolyl) acrylamide (118): HO H2N ao O N’N —- -— CI N’N ’ N) OAK o ' ,0 F30 \N’ F30 N/> \N NMM,THF, NH3 117 118 (E)(3—(3, 5—Bis orornethyl) phenyl)-1H—1, 2, 4—triaZ0l—1-yl)—2—(3, 5- dimethyl isoxazol—4—yl) rnide (118) was synthesized using General Procedure 3. (Yield: 0.015 g, 15 %). 1H NMR (400 MHZ, DMSO-d6) 6 9.09 (s, 1H), 8.39 (s, 1H), 8.30 (s, 2H), 8.27 (s, 1H), 7.53 (s, 1H), 7.37 (s, 1H) 2.33 (s, 3H), 2.17 (s, 3H). LCMS: m/z 490.27 [M+45]+, rR= 2.37 min.

Synthesis of isopropyl (E)(3—(3,S-bis(trifluor0methyl)phenyl)—1H—1,2,4-triaz01—1-yl)—2- (5-flu0r0pyridinyl)acrylate (119): ,rBr N \/é\OH N’//\ I A? I F30 / FSC "/2 " Pd(PPh3)ZC|2 D'10mm H 0 F3 7 2 F3 119 Isopropyl (E)-3—(3 -(3,5-bis(trifluorornethyl)phenyl)—1H—1,2,4—triazol—1—yl)-2—(5- fluoropyridin—3-yl)acrylate (119) was synthesized using l Procedure 6. (Yield: 0.2 g, 19 %). 1H NMR (400 MHZ, DMSO-d6) 6 9.21 (s, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 8.07 (s, 2H), 7.83—7.80(rn,1H)5.10-5.07(rn,1H), 1.27 (d, J: 6 HZ, 6H). LCMS: m/Z 489.32 [M+H]+, tR= 2.91 min.

W0 2014/205389 Synthesis of isopropy] (E)(3-(3,5—bis (trifluoromethyl)phenyl)—1H—1,2,4-triazolyl)— 2-(6—methoxypyridin-3—yl) acrylate (120): F52:0 HO _N / N’N Br :8 I N) HO ‘Q‘O 3)ZCl2 CchOOK, F3 7 Dioxane, H20 Isopropyl (E)(3—(3,5—bis (trifluorornethyl) pheny1)-1H~l, 2, 4-triazolyl)—2-(6- methoxypyridinyl) acrylate (120) was synthesized using General Procedure 6. (Yield: 0.14 g, 20%). 1H NMR (400 MHz, DMSO-dé) (3 9.12 (s, 1H), 8.51 (s, 1H), 8.23 (s, 1H), 8.14 (s, 2H), 8.07 (s, 1H), 7.62 (dd, J1, J; = 2.4 Hz, 1H), 6.87 (d, J: 8.4 Hz, 1H), 5.09-5.06 (m, 1H). 3.89 (s, 3H), 1.27 (d, J: 6 Hz, 6H). LCMS: m/z 501.33 [M+H]+, tR=3.06 min.

Synthesis of (E)(3—(3,5-bis(triflu0r0methyl)phenyl)-1H—1,2,4-triazol-1—yl)—2-(6- methoxypyridinyl) acrylic acid (121): (E)-3—(3-(3, 5~Bis oromethyl) phenyl)-1H~1, 2, 4—triazolyl)—2—(6- methoxypyridinyl) acrylic acid (121) was synthesized using General Procedure 2. (Yield: 0.1 g, 71%). 1H NMR (400 MHz, DMSO—dé) (3 13.25 (s, 1H), 9.09 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 8.14 (s, 2H), 8.06 (s, 1H), 7.60 (dd, J1, J2 = 2.4 Hz, 1H), 6.86 (dd, J1, J2 = 0.8 Hz,1H), 3.89 (s, 3H). LCMS: m/z 459.21 [M+H]+, tR=2.53 min.

Synthesis of pyl (E)(3-(3,5-bis (trifluoromethyl) )—1H—1, 2, 4—triazol-1—yl)- 2-(furan-3—yl) acrylate (122): >0 1 (2:0 O ,— B\ Br OH N’ O\/:r ' (2 hf, \ 0 F30 ____...__. F30 (2 Pd(PPh3)ZC|2 CHSCOOK, 7 Dioxane, H20 F3 F3 122 Isopropyl (E)(3-(3, 5—bis (trifluoromethyl) phenyl)-lH—l, 2, 4—triazol-1—yl)—2— (furan—3—yl) acrylate (122) was synthesized using General Procedure 6. (Yield: 0.2 g, 21%). 1H NMR (400 MHz, DMSO-dg) 5 8.93 (s, 1H), 8.42 (s, 2H), 8.26 (d, J: 10 Hz, 2H), 7.86 (s, 1H), 7.73 (s, 1H), 6.41 (dd, J1, J2 = 0.8 Hz, 1H), 5.10-5.07 (m, 1H), 1.30 (d, J: 6 Hz, 6H).

Synthesis of (E)—3—(3—(3,S-bis(trifluoromethyl)phenyl)—1H—1,2,4-triazolyl) (pyrimidin-S—yl) acrylic acid (123): NJ 0 H. ,N‘ 4 / THFH20 )4 F3 V (3-(3,5-Bis1(1trifluoromethyl)phenyl)—lH—l,2,4-triazol—1-yl)-2—(pyrimidin—5- yl) acrylic acid (123) was synthesized using General Procedure 2. (Yield: 0.15 g, 19%). 1H NMR (400 MHz, DMSO—d6) 5 13.52 (s, 1H), 9.23 (s, 1H), 9.18 (s, 1H), 8.77 (s, 2H), 8.69 (s, 1H), 8.26 (s, 1H), 8.07 (s, 2H). LCMS: m/z 430.0 [M+H]+, tR=2.21 min.

Synthesis of (E)(3-(3,S-bis(trifluor0methy1)phenyl)—1H—1,2,4—triazolyl)-2— (pyrimidin-S-yl)acrylamide (124): F c3 N:N\ N2N \ NMM THF NH3 )4 NV F3 V (E)(3-(3,5—Bis1(2trifluoromethyl)phenyl)-lH—1,2,4-triazol—1-yl)(pyrimidin—5- yl)acrylamide (124) was synthesized using General Procedure 3 (Yield: 0.03 g, 30%). 1H NMR (400 MHz, DMSO-dg) 5 9.21 (s, 1H), 9.14 (s, 1H), 8.73 (s, 2H), 8.43 (s, 1H), 8.24 (s, 1H), 8.06 (s, 2H), 7.65 (s, 1H), 7.40 (s, 1H). LCMS: m/z 429.13 [M+H]+, tR=2.14 min.

Synthesis of (3-(3,5-bis(triflu0r0methyl)phenyl)—1H-1,2,4-triazolyl)—2—(5- fluoropyridinyl)acrylic acid (125): >0 v N’ / \ N’ F30 1K2 LIOH.H20 t K? _’ F30 F THF/H20 F3 119 F3 125 (E)(3—(3,5—Bis(trifluoromethyl)phenyl)—1H—1,2,4-triazolyl)—2-(5— fluoropyridin—3-yl)acrylic acid (125) was synthesized using l Procedure 2 (Yield: 0.07 g, 64%). 1HNMR (400 MHz, DMSO d6)613.46(s, 1H), 9.18 (s, 1H), 8.63 (s, 1H), 8.58 (s, 1H), 8.35 (t, J: 3.5 Hz, 1H), 8.25 (s, 1H), 8.07 (s, 2H), 7.81—7.77 (m, 1H). LCMS: m/z 447.3 [M+H]+, m = 2.43 min.

Synthesis of 3—(3-(3,S-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-l-yl)(5- yridinyl)acrylamide (126): N, /\ CIAOAK F30 '(2 ~— F30 NMM,THF.NH3 F3 125 F3 126 (E)—3-(3-(3,5—Bis(trifluoromethyl)phenyl)-1H—1,2,4-triazol-1—yl)—2-(5— fluoropyridin-3—yl)acrylamide (126) was synthesized using General Procedure 3 (Yield: 0.04 g, 66%). 1H NMR (400 MHz, DMSO d6) 6 9.08 (s, 1H), 8.60 (d, J: 2.8 Hz, 1H), 8.37 (s, 1H), 8.43 (t, J= 1.6 Hz, 1H), 8.23 (s, 1H), 8.08 (s, 2H), 7.78—7.74 (m, 1H), 7.65 (s, 1H), 7.24 (s, 1H). LCMS: m/z 446.3 [M+H]', IR: 2.32 min.

Synthesis of (E)(3-(3,5—bis(trifloromethyl)phenyl)-lH-1,2, 4—triazolyl)-2—(6- methoxy pyridin—3—yl) acryl amide (127): CIAOY NMM. THF, NH3 (E)—3—(3-(3, 5-bis romethyl) phenyl)—1H—1, 2, 4-triazol-1—yl)—2-(6-methoxy pyridinyl) acryl amide (127) was synthesized using General Procedure 3 (Yield: 0.05 g, 36%). 1H NMR (400 MHz, g) 5 8.97 (s, 1H), 8.23 (d, J: 10 Hz, 2H), 8.16 (s, 2H), 8.04 (d, J: 0.8 Hz, 1H), 7.57 (dd, J1 = 2.4 Hz, J2 = 2.4 Hz, 2H), 7.17 (s, 1H), 6.88 (d, J: 8 Hz, 1H), 3.90 (s, 3H). LCMS: m/z 458.36 [M+H]+. tR=2.44 min.

Synthesis of (E)—3-(3—(3,5-bis(triflu0r0methyl)phenyl)—1H—1,2,4-triazol—1-yl)—2-(furan yl) acrylic acid (128): N’N ’— N’ I N) \ o LIOH.H20 I N) \ o Fgc F30 THF/HZO 122 . 123 "3 CF3 (E)—3—(3-(3,5—Bis (trifluoromethyl) phenyl)—1H—1, 2, 4—triazol—1—yl)—2-(furan—3-yl) acrylic acid (128) was synthesized using General Procedure 2 (Yield: 0.11 g, 81%). 1H NMR (400 MHz, DMSO-dg) 5 13.31 (s, 1H), 8.91 (s, 1H), 8.42 (s, 2H), 8.27 (d, J: 3.2 Hz, 2H), 7.84 (s, 1H), 7.70 (s, 1H), 6.40 (s, 1H). LCMS: m/z 416.25 [M-H]', tR=2.57 min.

Synthesis of (3-(3,5-bis(trifluoromethyl)phenyl)-1H—1,2,4-triazolyl)(furan yl) acrylamide (129): 0 )Ok 0 N’N> — — O/W/ N’N> FSC\EP/kNl / \ 0 l / \ o NMM, THF, NH3 HOUR] cpa 123 CF3 129 (E)—3-(3-(3,5-Bis (trifluoromethyl) pheny1)—1H-1, 2, 4-triazol—1—y1)—2—(furanyl) acrylamide (129) was sized using General Procedure 3 (Yield: 0.05 g, 50%). 1H NMR (400 MHz, DMSO-dg) 5 8.77 (s, 1H), 8.43 (s, 2H), 8.27 (s, 1H), 7.91 (s, 1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.46 (s, 1H). 6.29 (s, 1H).

Synthesis of isopropyl (E)(3-(3,5-bis(triflu0r0methyl)phenyl)—1H—1,2,4-triazolyl) (1-methyl-lH-pyrazolyl)acrylate (130): N—N N— ‘ F30 NA:% 31H: F30 l /) \ N 1311(1)th,,-14Dioxane N N’ \ C32CO3 H2O F C3 F30 7 130 pyl (E)(3—(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4—triazol-l-yl)-2—(1- methyl-lH—pyrazol—4-yl)acrylate (130) was synthesized using General Procedure 1 (Yield: 0.32 g, 13 %). 1H NMR (400 MHz, DMSO-dg) 5 8.96 (s, 1H), 8.43 (s, 2H), 8.29 (s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.41 (s, 1H), 5.10—5.07 (m, 1H), 3.86 (s, 3H), 1.31-1.24 (m, 6H). LCMS: m/z 474.37 , rR = 2.86 min.

Synthesis of (E)—3—(3-(3,5-bis(triflu0r0methyl)phenyl)—1H-1,2,4-triazol-1—yl)(1-methyl- 1H—pyrazol-4—yl)acrylic acid (131): >0 O N N—N — F30 N/>"1%\ N\ LIOH' H20. ' F30 N/> \N,N\ THF, H2O CF3 130 CFS 131 (E)(3~(3,5-Bis(triflu0r0methyl)phenyl)-lH—l,2,4—triaZOl—l—yl)(1~methyl-1H— pyrazolyl)acrylic acid (131) was synthesized using General Procedure 2 (Yield: 0.08 mg, 88 %). 1H NMR (400 MHz,DMSO—d6)513.25 (s, 1H), 8.93 (s, 1H), 8.43 (s, 2H), 8.28 (s, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.38 (s, 1H), 3.86 (s, 3H). LCMS: m/z 432.29 [M+H]+, tR = 2.32 min.

Synthesis of (E)(3-(3,5-bis(triflu0r0methyl)phenyl)—1H-1,2,4-triazolyl)(5- fluoropyridinyl)acrylamide (132): , o FSC 0* ‘ D Br2 N\ D Eth LuOH.

N ‘ ——> N —-> N11 \ o FSC CHZCIZ F3C THF N91 THF. H20 11 12 7 CF53 CF3 0H F c . 3 NH /N;l[\l \ Cl 0 / / ‘N \ O O /\r __~_N___> N9] Br /N:I\J/\(§O / N’ N’ Br Pd(dppf)Clz. AcOK F3 | F3 NMM‘ NHS' THF F3 dioxane, H20 \ N 14 15 132 Synthesis of isopropyl 3-(3-(3,5-bis(triflu0r0methyl)phenyl)—1H—1,2,4-triazol- 1-yl)-2,3—dibr0m0propanoate (12): opropyl 3,5-bis(trifluoromethyl)phenyl)-1H- 1,2,4-triazol'yl)acrylate (11) (100 g, 254.4 mmol) was dissolved in dichloromethane (500 mL) at room temperature. e (80 g, 500 mmol) was added dropwise over 40 min at 0 OC. The reaction mixture was allowed to warm to room temperature and stirred for 6 h. The reaction mixture was transferred into iced water and ted with CH2C12 (500 mL X 3).

The combined organic layers were washed with saturated sodium bisulphite aqueous solution (500 mL) followed by brine, dried over anhydrous Na2804 and concentrated under reduced pressure to give isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H—1,2,4- triazolyl)—2,3-dibromopropanoate (12), which was used in next step without further purification. (130 g, 93% yield). LCMS: m/Z 554.09 [M+H]+, 1R: 1.95 min. sis of (Z)-is0pr0pyl 3-(3-(3,5-bis(trifluor0methyl)phenyl)-1H—1,2,4- triazolyl)brom0acrylate (13): Isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H- 1,2,4—triazol-1—yl)-2,3-dibromopropanoate (12) (120 g, 217 mmol) was dissolved in tetrahydrofuran (350 mL) and cooled down to 0 OC. Triethylamine (44 g, 434 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (200 mL X 3). The ed organic layers were washed with brine, dried over ous Na2804 and concentrated under d pressure. The crude product was purified by recrystallization from 8% EtOAc in petroleum ether to get (Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H- 1,2,4-triazolyl)bromoacrylate (13) as white solid (90 g, 88% yield). 1H NMR (400 MHZ, DMSO-dg) 6 9.46 (s, 1H), 8.92 (s, 1H), 8.56 (s, 2H), 8.32 (s, 1H), 5.13-5.07 (m, 1H), 1.33 (d, J= 6 Hz, 6H). LCMS: m/z 472.0 [M+H]+, tR= 2.10 min.

Synthesis of (Z)—3-(3-(3,5-bis(trifluor0methyl)phenyl)-1H-1,2,4-triazol—1-yl) crylic acid (14): (Z)—isopropyl 3—(3-(3,5—bis(trifluoromethyl)phenyl)—1H—1,2,4- triazol—1—yl)—2—bromoacrylate (13) (40 g, 85 mmol) was ved in tetrahydrofuran (350 mL) and water (85 mL). Lithium hydroxide aqueous solution (20 mL, 254 mmol, 12.7 N) was added drop wise to the mixture at 0 0C. The reaction mixture was stirred at 0 0C for 1 h, and poured into water (100 mL), acidified with HCl (3 N) until pH = 3, extracted with ethyl acetate (200 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804, concentrated under reduced re, and purified by recrystallization from 20% EtOAc in petroleum ether to afford (Z)—3-(3-(3,5-bis(trifluoromethy1)phenyl)—1H— 1,2,4-triazol—1-yl)-2—bromoacrylic acid (14) as white solid (27 g, 75% yield). 1H NMR (400 MHz, DMSO-dg) 5 9.43 (s, 1H), 8.89 (s, 1H), 8.56 (s, 2H), 8.31 (s, 1H). LCMS: m/z 431.9 [M+H]+, 1R: 1.85 min.

] Synthesis of (Z)(3-(3,5-his(trifluoromethyl)phenyl)-lH-l,2,4-triazolyl) bromoacrylamide (15): (Z)—3—(3-(3,5-bis(trifluoromethyl)pheny1)—1H—l riazol—1-y1)-2— bromoacrylic acid (14) (50 g, 34.9 mmol) was ved in THF (400 mL) and yl chloroformate (31.7 g, 224 mmol), N-methyl morpholine (17.8 g, 175.5 mmol) were added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Ammonia gas was purged for 40 min at 0 °C. The reaction mixture was transferred into iced water and extracted with ethyl acetate (300 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804 and concentrated under reduced pressure to give crude product, which was purified by tallization from EtOAc to give 42 g of (Z)—3-(3—(3,5- bis(trifluoromethyl)phenyl)—lH—l,2,4-triazolyl)—2-bromoacrylamide (15). Yield: 85%. 1H NMR (400 MHz, DMSO-dg) 5 9.40 (s, 1H), 8.70 (s, 1H), 8.54 (s, 2H), 8.29 (s, 1H), 8.0- 7.95 (m, 2H). LCMS: m/Z 429.0 [M+H]+, zR= 1.78 min.

Synthesis of (E)(3-(3,5—bis(trifluor0methyl)phenyl)-lH-l,2,4-triazol-1—yl)- 2-(5—flu0ropyridinyl)acrylamide (132): (E)-3—(3—(3,5-bis(trifluoromethyl)phenyl)-1H— 1,2,4-triazolyl)—2—(5—fluoropyridinyl)acrylamide (132) was synthesized according to General Procedure 6. Yield: 6%. 1H NMR (400 MHz, DMSO—dg) 8 9.08 (s, 1H), 8.60 (d, J = 3 Hz, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 8.08 (s, 2H), 7.76 (d, J= 9 Hz, 1H), 7.63 (s, 1H), 7.24 (s, 1H). LCMS: m/z 446.1 [M+H]+, 1R = 1.70 min. —96- Synthesis of (E)(3—(3,5-bis(trifluor0methyl)phenyl)—1H—1,2,4-triazol—1-yl) (pyridazin—4-yl)acrylamide (133): F:©\S\1:’N\Br mi 2H Pd(dppf012 AcOK 530% dioxane H20 [003 16] (E)—3 —(3 bis(trifluoromethyl)pheny1)—1H—1,2,4-triazol-1—y1)—2—(pyridazin yl)acrylamide (133) was synthesized according to General Procedure 6. Yield: 2%. 1H NMR (400 MHZ, DMSO-d6) 8 9.28 (dd, J; = 5 Hz, J2 = 1 Hz, 1H), 9.17-9.09 (m, 2H), 840 (s 1H) 8.22 (s 1H), 8.02 (s, 2H), 7.70—7.61 (m, 2H), 7.36 (s, 1H). LCMS: m/z 429.1 [M+H]+, 1R: 1.54 min.

Synthesis of (E)-3—(3-(3,5—bis(trifluoromethyl)phenyl)-1H—1,2,4—triazol-1—yl)-2—(6- fluoropyridin-Z-yl)acrylamide (134): (I) /N\grid/$2M F30©\filF3C Pd(()AcOdeprlz, IN F3C dioxane H20 (E)-3~(3—(3,5-bis(trifluoromethy1)phenyl)—1H—1,2,4—triazol—1-y1)-2—(6- fluoropyridin-2—yl)acrylamide (134) was synthesized according to General Procedure 6.

Yield: 40%. 1H NMR (400 MHZ, DMSO—ds) 8 9.17 (s, 1H), 8.54 (s, 2H), .23 (m, 2H), 8.14-8.00 (111,211), 7.91 (s, 1H), 7.47—7.39 (m, 24—7.17(m, 1H). LCMS: m/Z 446.1 [M+H]+, 1R: 1.84 min.

Synthesis of (E)(3-(3,5-bis(trifluor0methyl)phenyl)—1H—1,2,4-triazolyl)—2—(2- fluoropyridin-3—yl)acrylamide (135): /\/g2_~__>\/B: N\ / j] 0 Pd(()dppf012 AcOK F30 (1 dioxane H20 \ WO 05389 (E)—3-(3—(3,5-bis(trifluoromethy1)pheny1)-1H-1,2,4-triazol—1—y1)—2—(2— fluoropyridin—3-y1)acry1amide (135) was synthesized according to General Procedure 6.

Yield: 14%. 1H NMR (400 MHZ, CD3OD) 8 8.90 (s, 1H), 8.42 (s, 1H), 8.34 (d, J: 4 HZ, 1H), 8.19 (s, 2H), 8.02 (s, 1H), 7.97—7.88 (m, 1H), 7.52-7.42 (m, 1H). LCMS: m/z 446.1 [M+H]+, 1R = 1.82 min.

Synthesis of (E)(2-aminopyrimidin—S-yl)—3-(3-(3,5-bis(trifluoromethyl)phenyl)—1H— triazolyl)acr'ylamide (136).

F30 NH2 F c N 0 3 NHZ H2N~<\ :/>—B: N\ / N \ O / N \ O 9’ 9’ / Br Pd(dppf)C12, ACOK F30 F c ' N \ [I 3 e, H20 136 \r [003 1 9] (E)—2—(2—aminopyrimidin—5-y1)—3-(3—(3 ,5—bis(trifluoromethy1)phenyl)-1H—1,2,4— triazol—l-yl)acry1amide (136). Yield: 25%. 1H NMR (400 MHZ, DMSO—d6) 8 9.01 (s, 1H), 8.30 (s, 2H), 8.25 (s, 1H), 8.14 (s, 1H), 8.07 (s, 2H), 7.52 (s, 1H), 7.40 (s, 1H), 6.79 (s, 2H).

LCMS: m/z 444.1 [M+H]+, 1R = 1.64 min.

Synthesis of (E)—3-(3-(3,S-bis(trifluoromethyl)phenyl)—lH-l,2,4-triazolyl)(2- pyrimidin—S-yl)acrylamide (137): N.. F30 [OH NH2 F C3 NH F 2 ~—B/ \OH ,N‘N \ O / \N O _________._, N9, 9’ / Br Pd(dppf)Cl2, ACOK F30 [1 F3C dioxane, H20 NY 137 (E)—3—(3—(3,5-Bis(trifluoromethyl)pheny1)—1H—1,2,4-triaZ01—1-y1)—2—(2— fluoropyrimidin-5—y1)acry1amide (137) was synthesized according to General Procedure 6.

Yield: 18%. 1H NMR (400 MHZ, DMSO—d6) 8 9.19 (s, 1H), 8.75 (s, 2H), 8.48 (s, 1H), 8.25 (s, 1H), 8.09 (s, 2H), 7.67 (s, 1H), 7.36 (s, 1H). LCMS: m/z 447.1 [M+H]+, tR= 1.81 min.

Synthesis of (E)—3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H—1,2,4-triazol—1-yl)-2—(3- fluoropyridin—4-yl)acrylamide (138): _ 98 _ F F3C NH2 F30 NH2 -— P" N N N\ / B\ / \N O 9’ Br f)C|2, ACOK F30 I F30 dioxane, H20 \N 133 (E)—3—(3—(3,5—bis(trifluoromethy1)pheny1)—1H-1,2,4-triazoI—1-y1)(3- fluoropyridin—4—y1)acrylamide (138) was synthesized according to generap procedure 6.Yie1d: 1H NMR (400 MHz, CD30D) 8 8.78 (s, 1H), 8.48 (s, 1H), 8.41 (d, J: 5 Hz, 1H), 8.34 (s, 1H), 8.06 (s, 2H), 7.92 (s, 1H), 7.43—7.37 (m, 1H). LCMS: m/z 446.0 [M+H]+, IR = 1.69 min.

Synthesis of (E)-3—(3—(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4—triazol-1—yl)(6- fluoropyridin—3—yl)acrylamide (139).

F3C NH2 FQBEZN.— N\ / NN/go ._______, 9, Br Pd(dppf)C|2, ACOK F3C dioxane H20 (E)—3-(3-(3,5—bis(trifluoromethyl)pheny1)—1H—1,2,4-triazoly1)—2—(F6- fluoropyridin—3—y1)acry1amide (139) was synthesized according to General Procedure 6.

Yield: 15%. 1H NMR (400 MHz, CD30D) 8 8.80 (s, 1H), 8.37 (s, 1H), 8.24 (s, 2H), 8.19 (d, J: 2 Hz, 1H), 8.03 (s, 1H), 7.98—7.90 (m, 27—7.19(m, 1H). LCMS: m/z 446.1 [M+H]+, IR = 1.84 min.

Synthesis of (3-(3,5—bis(trifluor0methyl)phenyl)—1H—1,2,4—triazol—1—yl)(2— fluoropyridin-4—yl)acrylamide (140).

F F30 0 F3C OH NH2 NOBOH /N\N \ NHz \N \ o A / ___________, 9’ / Br Pd(dppf)C|2,AcOK F30 I F30 dioxane, H20 N F 140‘ (E)—3-(3—(3,5-bis(trifluoromethy1)phenyl)-1H—1,2,4-triazoly1)—2-(2-i fluoropyridiny1)acrylamide (140) was synthesized according to General Procedure 6.

Yield: 29%. 1H NMR (400 MHz, CD3OD) 8 8.79 (s, 1H), .30 (rn, 2H), 8.23 (s, 2H), 8.03 (s, 1H), 7.33 (d, J= 5 Hz, 1H), 7.17 (s, 1H). LCMS: m/z M+H]+, 7R: 1.84 min.

Synthesis of (E)—3-(3-(3,S-bis(trifluoromethyl)phenyl)-lH—l,2,4-triazol-1—yl)(5— ch10r0pyridin-3—yl)acrylamide (141).

F C3 NH2 ’- [O _}\l————-—->/ B\(): ‘N 9’ Br , Pd(dppf)Clg,AcOK F3C e, H20 (E)-3—(3—(3,5-bis(trifluoromethyl)phenyl)—1H-1,2,4-triazolyl)-2—(5— chloropyridin—3—y1)acry1amide (141) was synthesized according to l Procedure 6.

Yield: 31%. 1H NMR (400 MHz, DMSO-d6) 8 9.10 (s, 1H), 8.65 (d, J: 2 Hz, 1H), 8.40 (d, J: 2 Hz, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 8.08 (s, 2H), 798—91 (In, 1H), 7.62 (s, 1H), 7.27 (s, 1H).

LCMS: m/z 462.0 [M+H]+, 2R = 1.76 min.

Synthesis of (E)(3-(3,S—bis(trifluor0methyl)phenyl)—1H-1,2,4-triazolyl)—2-(6- ch10r0pyridinyl)acrylamide (143): F3C O F3C NH2 /N\N/\/go GIG—Bf}! \ / \N NH \ 2 N OH 9’ —"'——‘—"" J / N’ Br Pd(dppf)C|2, AcOK F30 \ Ll F3C dioxane, H20 143 (E)—3—(3—(3,5-bis(trifluoromethy1)pheny1)-1H—1,2,4—triazol—1-y1)(6- chloropyridin-3—yl)acry1amide (143) was synthesized according to General Procedure 6.

Yield: 24%. 1H NMR (400 MHz, DMSO-dg) 8 9.09 (s, 1H), 8.35 (s, 1H), 8.30 (d, J= 2.0 Hz, 1H), 8.22 (s, 1H), 8.10 (s, 2H), 7.80-7.74 (In, 1H), 7.65-7.55 (in, 2H), 7.24 (s, 1H). LCMS: m/z 462.0 [M+H]+, 2R = 1.77 min.

Synthesis of (E)(3-(3,5—bis(triflu0r0methyl)phenyl)-1H—1,2,4-triazol—1-yl)—2-(2- chloropyridin-3—y1)acrylamide (144): \ / N\ Bio / N \ o ‘N 9! Br Pd(dppf)C|2, AcOK N:—12 F3C dioxane H20 (E)-3 -(3 -(3 ,5 —bis(trif1uoromethyl)phenyl)-1H-1,2,4-triazol-1—yl)—2—(2- chloropyridin—3—y1)acry1amide (144) was synthesized according to General Procedure 6.

Yield: 4%. 1H NMR (400 MHz, CD3OD) 5 8.89 (s, 1H), 8.54—8.49 (m, 1H), 8.42 (s, 1H), 8.17 (s, 2H), 8.03 (s, 1H), 7.88—7.83 (m, 1H), 7.57-7.52 (m, 1H). LCMS: m/z 462.0 [M+H]+, m— 1.70 min.

Synthesis of (E)(3-(3,5-bis(triflu0r0methyl)phenyl)—1H-1,2,4-triaz01—1-yl)(2,6- difluor0pyridinyl)acrylamide (145):F , ‘N o ,1 4’ Br Pd()AcOdeprlz, F30 F30 dioxane, H20 ] (E)—3-(3-(3,5~bis(trifluoromethy1)pheny1)—1H—1,2,4-triazoly1)(2,6- difluoropyridin—3—y1)acry1amide (145) was synthesized according to General Procedure 6.

Yield: 5%. 1H NMR (400 MHz CD3OD) 5 8. 80 (s 1H) 832 (s 1H) 8.12 (s 2H) 7.95-7.86 (m 2H) 7.01 (dd J1: 8 Hz J2_* 2Hz 1H). LCMS: m/z 464. 0 , tR=1.74 min. sis of (E)(3-(3,S-bis(trifluor0methyl)phenyl)-1H—1,2,4-triazolyl)—2— phenylacrylamide (146): F3C NH2 I .. Si oat: / N O 91 Br Pd(dppf)CI2 AcOK F3C dioxane H20 (E)-3 —(3 -(3 ,5 ~bis(trifluoromethy1)pheny1)-1H—1,2,4-triazol— 1 — phenylacrylamide (146) was synthesized according to General Procedure 6. Yield: 32%. 1H NMR (400 MHz, CD30D) 5 8.24 (s, 2H), 8.11 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.49-7.40 (m, 3H), 7.30—7.21 (111,214). LCMS: m/z 427.1 [M+H]+, :2 = 2.10 min.

Synthesis of (E)-3—(3~(3,5-bis(triflu0r0methyl)phenyl)-1H~1,2,4-triazolyl)—2-(2- (trifluor0methyl)pyridin—4-yl)acrylamide (147): F3C NH2 N>\:>,BOHOH\ / / \NVO A Br Pd(dppf)Cl2, ACOK F3C e, H20 (E)(3-(3,5-bis(trifluorornethyl)phenyl)-lH—l,2,4-triazolyl)—2-(2- (trifluorornethyl)pyridin—4-yl)acrylarnide (147) was synthesized according to General procedure 6. Yield: 11%. 1H NMR (400 MHZ, DMSO-dg) 5 9.13 (s, 1H), 8.81 (d, J: 5 Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 8.00 (s, 2H), 7.88 (s, 1H), 7.66 (s, 1H), 7.61 (d, J: 5 Hz, 1H), 7.25 (s, 1H). LCMS: m/Z 496.0 , 1R = 1.79 min.

Synthesis of (E)~3—(3—(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1—yl)(5- cyanopyridinyl)acrylamide (148): FsC NH2 2}:/ B \N / \NVOM 9! Br Pd(dppf)CI2, ACOK F3C dioxane, H20 (3-(3,5-bis(trifluorornethyl)phenyl)-1H—1,2,4-triazolyl)(5— cyanopyridin—3—yl)acrylarnide (148) was synthesized according to General Procedure 6.

Yield: 20%.1H NMR (400 MHZ, DMSO-dg) 6 9.14 (s, 1H), 9.06 (d, J: 2 Hz, 1H), 8.75 (d, J = 2 Hz, 1H), 8.43 (s, 1H), 8.37-8.32 (m, 1H), 8.23 (s, 1H), 8.03 (s, 2H), 7.66 (s, 1H), 7.27 (s, 1H).

LCMS: m/Z 453.1 [M+H]+, 12: 1.79 min.

Synthesis of (E)-3—(3-(3,5-bis(triflu0r0methyl)phenyl)—1H-1,2,4—triazol-1—yl)—2-(quin01in— 3-yl)acrylamide (149): — 102 - F30 O :N—/>—3::: \ / \N NH2 Pd(()dppf)Clz, ACOK F30 1 dioxane H20 N\ [0033 l] (E)—3 —(3—(3 ,5 —bis(trifluoromethyl)pheny1)—1H—l,2,4—triazol—1—yl)—2—(quinolin—3- ylamide (149) was synthesized according to General Procedure 6. Yield: 80%. 1H NMR (400 MHz, DMSO-dg) 5 9.09 (s, 1H), 8.75 (d, J: 2 Hz, 1H), 8.42 (s, 1H), 8.29 (d, J: 2 Hz, 1H), .97 (m, 3H), 7.88 (s, 2H), 7.82 (t, J: 7 Hz, 1H), 7.63 (t, J: 7 Hz, 2H), 7.31 (s, 1H). LCMS: m/z 478.1 [M+H]+, 1R: 1.64 min.

Synthesis of (E)—3-(3-(3,5-bis(trifluoromethyl)phenyl)—lH-l,2,4-triazol—l—yl)(2— fluorobiphenyl-4—yl)acrylamide (150): F oHH8‘0 F30 NH2 NEVO’ Br Pd(dppf)C|2,AcOK dioxane, H20 (E)—3 —(3—(3,5 —bis(trifluoromethyl)phenyl)-1H—1,2,4-triazol—1—yl)—2—(2— iphenyl—4—yl)acrylamide (150) was synthesized according to General Procedure 6.

Yield: 30%. 1H NMR (400 MHz, DMSO-d6) 6 8.89 (s, 1H), 8.23-8.18 (m, 4H), 7.63—7.56 (m, 4H), 7.54—7.48 (m, 2H), 7.47—7.40 (m, 1H), 7.31—7.25 (m, 1H), 7.20—7.14(m, 2H). LCMS: m/z 521.1 [M+H]+, 1R: 2.06 min.

Synthesis of (E)(3—(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol—1-yl)—2-(4- (pyridin—3-yl)phenyl)acrylamide (151): -lO3- N\3%; W82: flp‘fiy Pd((dppf)CI2 ACOK dioxane H20 115 / ] (E)—3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH—l,2,4-triazol-l-yl)—2-(4-(pyridin yl)phenyl)acrylamide (151) was synthesized according to General Procedure 6. Yield: 11%. 1H NMR (400 MHz, CD30D) 5 9.19 (s, 1H), 8.84-8.74 (m, 2H), 8.52 (s, 1H), 8.31—8.26 (m, 3H), 8.07-7.95 (m, 4H), 7.59 (d, J: 8 Hz, 2H). LCMS: m/z 504.1 [M+H]+, IR: 1.55 min.

Synthesis of (E)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)—2-(1H- indazol-6—yl)acrylamide (152): ~ N\3%; iZB‘Q/l N:N \ f)CI2, ACOK dioxane, H20 ‘NNH (3—(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-l—yl)(lH-indazol yl)acrylamide (152) was synthesized according to General Procedure 6. Yield: 46%. 1H NMR (400 MHZ, DMSO-dg) 5 8.54 (s, 1H), 8.20—8.10 (m, 3H), 8.06 (s, 2H), 7.85 (d, J: 8 Hz, 1H), 7.47 (s, 1H), 6.98 (d, J: 8 Hz, 1H). LCMS: m/z 467.1 [M+H]+, IR=1.67 min.

Synthesis of (Z)(3-(3,5-bis(triflu0r0methyl)phenyl)-1H—1,2,4-triazolyl) (pyrimidinyl)acrylamide (153): F30 Br F30 i r Eth Cl 0 / 31);: 16:N/j::r’ LiOH / LIE/1% fi/ / / F3 o THF H20 0 0H NMM. NH3.THF 12 17 F30 / \ }B: \ Wk Eq/OXNHZBI' Synthesis of (E)—3—(3—(3,5-bis(trifluoromethyl)phenyl)-1H—1,2,4—triazol-1—yl)- 2-br0moacry1ic acid (17): (E)-isopropyl 3—(3-(3,5—bis(trifluoromethyl)phenyl)-lH—1,2,4- triazol-l-yl)—2—bromoacrylate (16) (2.36 g, 5 mmol) was dissolved in tetrahydrofuran (25 mL). A solution of m hydroxide (1.05 g, 25 mmol) in water (25 mL) was added drop wise at 0 0C. The reaction mixture was stirred at 0 0C for 3 h, and poured into water (30 mL), acidified with HCl (3 N) until pH = 5, extracted with ethyl acetate (200 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804, ‘concentrated under reduced pressure, and purified by recrystallization from 20% EtOAc in petroleum ether to afford (3—(3,5-bis(trifluoromethyl)phenyl)-1H—1,2,4-triazolyl)~2- bromoacrylic acid (17) as white solid (1.2 g, 56% yield). 1H NMR (400 MHz, DMSO-d‘g) 5 8.98 (s, 1H), 8.49 (s, 1H), 8.29 (s, 2H), 8.00 (s, 1H). LCMS: m/z 433.0 [M+H]+, tR= 1.81 min.

Synthesis of (E)(3-(3,5-bis(trifluoromethyl)phenyl)—1H—1,2,4—triazolyl)— 2-br0m0acry1amide (18): (E)(3 bis(trifluoromethyl)phenyl)-1H-1,2,4-triazolyl)- 2-bromoacrylic acid (17) (0.9 g, 2.1 mmol) was dissolved in THF (20 mL) and isobutyl chloroformate (0.57 g, 4.2 mmol), N—methyl morpholine (0.32 g, 3.1 mmol) were added at 0 OC. The reaction mixture was d at 0 0C for 1 h. Ammonia gas was purged for 40 min at 0 OC. The reaction mixture was transferred into iced water and ted with ethyl e (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2804 and concentrated under d pressure to give crude product, which was purified by tallization from EtOAc to give 0.8 g of (E)(3—(3,5-bis(trifluoromethyl)phenyl)- 1H—l,2,4-triazol—l—yl)bromoacrylamide (18). Yield: 90%. 1H NMR (400 MHZ, DMSO- dg) 5 8.88 (s, 1H), 8.49 (s, 1H), 8.29 (s, 2H), 8.01 (s, 1H), 7.87 (s, 1H), 7.81 (s, 1H).

LCMS: m/Z 429.0 , rR= 1.80 min.

Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4—triazolyl) (pyrimidinyl)acrylamide (153). A mixture of (E)-3—(3—(3,5-bis(trifluoromethyl)phenyl)— lH-l,2,4—triazolyl)—2—bromoacrylamide (18) (600 mg, 1.4 mmol), pyrimidinylboronic acid (261 mg, 2.1 mmol), potassium acetate (277 mg, 2.8 mmol), [l,l'— bis(diphenylphosphino)ferrocene]palladiun1~(ll) chloride (91 mg, 0.11 mmol) in dioxane (60 mL) and water (5 mL) was heated at 80 0C for 45 s under nitrogen atmosphere. The mixture was poured into 30 mL of water and extracted with ethyl acetate (10 mL X 3). The ed organic layers were washed with brine, dried over anhydrous NaZSO4, concentrated under reduced pressure and purified by Prep-HPLC to afford (Z)—3-(3-(3,5— bis(trifluoromethyl)phenyl)-lH—l,2,4-triazol—1—yl)(pyrimidin—5-yl)acrylamide (153) (130 8.96 (s, 3H), 8.54 (s, 2H), mg, 22% yield). 1H NMR (400 MHz, DMSO-d6) 5 9.22 (s, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H). LCMS: m/z 429.1 [M+H]+, IR: 1.67 min.

Synthesis of (Z)(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol—1-yl)—2-(6- fluoropyridinyl)acrylamide (154): N_. OH F c3 F N\ Br FQ—B: xN1 /JN/:[ OH /N\N \ \ 0 4’ F3 NH2 Pd(dppf)C|2,AcOK o NH dioxane, H20 F3 2 18 154 (Z)(3-(3,5-bis(trifluoromethyl)phenyl)—1H—1,2,4-triazol-l-yl)(6- fluoropyridinyl)acrylamide (154) was synthesized according to General Procedure 6.

Yield: 7%. 1H NMR (400 MHZ, CD3OD) 5 8.70 (s, 1H), 8.56 (s, 2H), 8.34 (d, J: 3 Hz, 1H), .03 (m, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 7.11—7.05 (m, 1H). LCMS: m/z 446.1 [M+H]+, IR: 1.68 min. 2014/043479 ~106— sis of (Z)—3-(3—(3,5-bis(triflu0r0methyl)phenyl)-lH—l,2,4-triazolyl)(2- flu0r0pyridinyl)acrylamide (155): _ pH F30 / N /N:21Br N\ / B‘ I N OH N \ / ‘N NH2 Pd(dppf)C|2, AcOK A dioxane,H2O F3 NH2 ] (Z)—3-(3-(3,5-bis(trifluorornethyl)phenyl)—lH—l,2,4—triazol-l—yl)—2—(2- fluoropyridin—4—yl)acrylarnide (155) was aynthesized according to General Procedure 6.

Yield: 30%. 1H NMR (400 MHz, CD30D) 5 8.75 (s, 1H), 8.57 (s, 2H), 8.18 (d, J: 5 Hz, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.47—7.40 (m, 1H), 7.19 (s, 1H). LCMS: m/z 446.1 [M+H]+, IR: 1.79 min.

Synthesis of (Z)(3—(3,S-bis(triflu0r0methyl)phenyl)-1H-l,2,4-triazol-l-yl)(6- ch10r0pyridinyl)acrylamide (156).

F30 0' ("flaw— ,OH F3C / /N‘N \ Br N\ \ lv 9, ——-————-————> / N 0 A F3 NH2 Pd(dppf)CI2,AcOK 0 NH dloxane, H20 F3 2 18 156 (Z)-3—(3—(3,5-bis(trifluoromethyl)phenyl)—lH—l,2,4—triazol-1—yl)(6- chloropyridin—3-yl)acrylarnide (156) was synthesized according to General procedure 6.

Yield: 7%. 1H NMR (400 MHZ, DMSO-d6) 5 8.94 (s, 1H), 8.60 (d, J: 2 Hz, 1H), 8.54 (s, 2H) 8. 30 (s 1H) 8.06 (s 1H) 8. 02—7. 97 (In, 1H) 7.93 (s, 1H), 7.89 (s, 1H), 7.65 (d, J: 8 Hz 1H). LCMS: m/z 462.1 [M+H]+, IR=1. 82 min.

Synthesis of (Z)(3-(3,5—bis(trifluoromethyl)phenyl)—lH-l,2,4-triaz01—l-yl)—2-(2- flu0r0pyridin—3-yl)acrylamide (157): F30 {lj-gHOH F F30 /N B l /N\N \ Br / N\ \ 9, ’ 0 NH2 Pdd( ppf)CI AOK //'I\l, 2. c F3 0 F3 NH2 dioxane, H20 2014/043479 (Z)(3-(3,5-bis(trifluoromethyl)phenyl)—lH—l,2,4-triazol-l—yl)—2—(2— yridin-3~yl)acrylamide (157) was synthesized according to General ure 6.

Yield: 29%. 1H NMR (400 MHz, DMSO—d6) 6 9.06 (s, 1H), 8.60 (s, 2H), 8.38—8.33 (m, 2H), 8.20—8.11 (m, 1H), 8.03 (s, 1H), .81 (m, 2H), 7.60-7.51 (m, 1H). LCMS: m/z 446.1 [M+H]+, rR =1,69 min.

Example 2. Assays Certain compounds of the invention were tested in various assays.

Inhibition ofNuclear Export — Rev-GFP Assay ] The inhibition of CRM1 mediated nuclear export by compounds of the ion was determined in a RevGFP assay. Rev is a protein from human immunodeficiency virus type 1 (HIV—1) and contains a nuclear export signal (NES) in its C—terminal domain and a nuclear zation signal (NLS) in its N-terminal domain. Nuclear export of Rev protein is dependent on the classical NBS/CRM1 pathway (Neville et al, 1997, Kau et al, 2003).

Nuclear and nucleolar accumulation of Rev is observed in cells treated with specific inhibitors of CRM1, such as LMB (Kau et al, 2003).

In this assay, U2OS—RevGFP cells were seeded onto clear-bottom, black, 384—well plates the day before the ment. Compounds were serially diluted 1:2 starting from 40 uM in a separate 384—well plate in DMEM, and then transferred onto cells. Cells were incubated with compound for approximately 1 hour before fixation with 3.7% formaldehyde and nuclei staining with Hoechst 3325 8. The amount of GFP in cell nuclei was measured and compound leos were determined (Kau et al, 2003). The results of this assay are shown in Table 1.

In a separate ment, U2OS Rev-GFP cells were treated with Compound 124 (that was serially diluted 1:3 starting from 10 uM) or DMSO for 4 hours. After 4 hours, the cells were fixed with paraformaldehyde (PFA) and counterstained with the nuclear dye DAPI. Using dose-response curves, the ICso for Compound 124 was determined to be about 40 nM in the U2OS Rev—GFP assay. Thus, Compound 124 recapitulates the CRM1 inhibition observed using LMB, and ent with Compound 124 results in nuclear Rev— GFP. -108— MTT Cell Proliferation Assay The MTT cell proliferation assay was used to study the cytotoxic properties of the nds. The assay was performed according to the method described by Roche Molecular Biochemicals, with minor modifications. The assay is based on the cleavage of the tetrazolium salt, MTT, in the presence of an electron—coupling reagent. The water—insoluble formazan salt produced must be solubilized in an additional step. Cells grown in a l tissue culture plate were incubated with the MTT solution for approximately 4 hours. After this tion period, a water—insoluble an dye formed. After solubilization, the formazan dye was tated using a scanning multi-well spectrophotometer (ELISA reader). The absorbance revealed directly correlates to the cell number. The cells were seeded at 5,000-10,000 cells in each well of l plate in 100 [L of fresh culture medium and were allowed to attach overnight. The stock solutions of the nds were diluted in 100 uL cell culture medium to obtain eight concentrations of each test compound, ranging from 1 nM to 30 uM. After incubation for approximately 64—72 hours, 20 uL of ter 96 Aqueous One Solution Reagent ga, G358B) was added to each well and the plate was returned to the incubator (37 °C; 5% C02) until an absolute OD of 1.5 was reached for the control cells. All optical densities were measured at 490 nm using a Vmax Kinetic Microplate Reader (Molecular Devices). In most cases, the assay was performed in duplicate and the results were presented as a mean percent tion to the negative control::SE. The following formula was used to calculate the percent of inhibition: Inhibition (%) = (1— (ODO/OD)) X 100.

The compounds were tested against 2138, MMl S and 3T3 cells. The 2138 cell line is a mature B-cell acute lymphoblastic leukemia cell line derived from a patient with chronic lumphocytic leukemia. The MMl S cell line was established from the peripheral blood of a human multiple myeloma patient. 3T3 cells are standard fibroblast cells; they were originally isolated from Swiss mouse embryo tissue.

The results of the MTT assay are ed in Table 1.

Table 1. Assay Results for ary Compounds (A = <100 nM; B = 100 nM to <5 "M; C = 5 [LM to 30 "M; D = >30 "M; NT = Not tested).

Cmpd. MTT MTT Structure " RevGFP l (MTT Name No. 2138) (MM15) (3T3) —109— Cmpd. MW MW MTT Structure RevGFP Name No. (2138) (MMlS) (3T3) _l CN ’1 1— 3-(3—(3,5- bis(trifluoromethy|)phenyl)— 100 D 1H—1,2,4—triazoI—l—yI)—2— (pyridin—Z—yl)acrylonitriIe isopropyl (E)—3—(3—(3,5— bis(trifluoromethyl)pheny|)— 1H—1,2,4—triazol—1-y|)-2— (pyridin—3—yl)acry|ate CF3 "##7## (E)—3-(3—(3,5— I bis(trifluoromethyl)phenyl)— 102 F30 / 1H—1,2,4-triazo|~1-yl)—2— (pyridin—3-yl)acry|onitrile (E)—3—(3—(3,5— bis(trifluoromethyl)phenyl)— 103 I / NT F30 1H-1,2,4—triazoIyI)—2— (pyridin—3—yl)acry|icacid ' CF3 J (E)—3—(3—(3,5— bis(trifluoromethyl)phenyl)— 104 ’ F3C / 1H-1,2,4—tr'|azoI—l—yl)—2— in—3—yl)acry|amide (E)—3—(3—(3,5— ’ bis(trifluoromethy|)phenyl)— 105 F3C / NT 1H—1,2,4—triazol~1—y|)—2— (pyridin—4-yl)acry|onitrile isopropyl (E)-3—(3-(3,5— ifluoromethyl)phenyl)— 106 NT NT ,4—triazol—1—yI)—2— (pyridin-4—yl)acrylate PCT/USZOl4/043479 MTI' Name (3T3) (E)—3-(3-(3,5— bis(trifluoromethy|)pheny|)— F3C NT NT 1H—1,2,4—triazoI—l—yl)—2— (pvridin-4—vl)acrylic acid (E)-3—(3-(3,5- bis(trifluoromethyl)pheny|)~ 1H-1,2,4-triazoI—1—yl)—2— (pyridin—4—yl)acrylamide a: isopropyl (Z)—3-(3—(3,5— N— S bis(trifluoromethy|)phenyl)— 109 ’rf [\L) NT NT B NT F3C ,4—triazoI-l—yl)—2— (thiazoI-Z-yl)acrylate CN _—f————-——7 [His (z)-3—(3—(3,5— / .

PC I) N\2 bIs(trIf|uoromethyl)phenyl)—v 110 3 NT NT B NT N 1H—1,2,4—triazoI—1—yl)—2— (thiazoI—2—y|)acrylonitriIe (3—(3,5— N—NPg:S bis(trifluoromethyl)phenyl)— / / 111 F30 N/ NJ A NT A D 1H—1,2,4—triazoI—l—y|)—2— (thiazoI—Z—y|)acrylamide 0 / N\ (E)—3—(3—(3,5- ~— if|uoromethyl)phenyl)— 112 // / \N NT NT D NT F30 1H—1,2,4—triazol—1-\/|)—N,N— N __ dimethyI—Z—(pyridin-3— y|)acrylamide CF3 _j 0 / N\ (E)-3—(3—(3,5— ’ bis(trif|uoromethyl)phenyl)— 113 F30 // / \ c NT B NT 1H—1,2,4—triazoI-l—y|)—N,N— N "N dimethyl—Z—(pyridin—4— y|)acrylamide 2014/043479 Cmpd. MTT MTT M'l'l' Structure Re"GFP Name (2138) (MM15) (3T3) (3—(3,5— bis(trifluoromethy|)phenyl)— 114 NT F30 1H—1,2,4—triaZOI—1—y|)—2—( 1— methyl—1H—pyrazoI—4— y )acrylamide| pyl (3-(3,5— bis(trifluoromethyl)phenyl)— 115 NT F30 1H—1,2,4-triazoI—1—yI)—2— (pyrimidin-S—yl)acrylate ____________fi__‘_ isopropyl (E)-3—(3—(3,5— bis(trifluoromethyl)phenyl)— 116 NT 1H—1,2,4—triazol—1—yl)-2—(3,5— dimethylisoxazoI—4- yl)acrylate _T———— (E)—3-(3—(3,5— bis(trifluoromethyl)phenyl)- 117 NT NT D NT 1H—1,2,4—triazoI—1—yl)(3,5— dimethylisoxazol—4—yl)acrylic acid CF3 +~A————————— (E)—3—(3—(3,5— bis(trifluoromethyl)phenyl)- 118 1H—1,2,4—tr'lazoI—1-yl)—2—(3,5— dimethylisoxazoI—4— y|)acry|amide isopropyl (E)—3—(3—(3,5— bis(trifluoromethyl)phenyl)— 1H—1,2,4—triazoI—1—y|)—2—(5- fluoropyridin-3—yl)acry|ate _L__J_____fi isopropyl (E)—3—(3—(3,5— bis(trifluoromethyl)pheny|)— F30 1H—1,2,4—triazoI—1—yl)—2—(6— methoxypyridin—3—yl)acrylate Cmpd. MTT MTT MTT ure ReVGFP Name No. (2138) (MMIS) (3T3) (E)—3—(3—(3,5- bis(trifluoromethy|)phenyl)— 121 NT NT D NT 1H-1,2,4—triazol—1—yl)—2—(6— methoxypyridin-3—yi)acry|ic acid pyl (E)—3—(3—(3,5— bis(trifluoromethyl)phenyl)— 122 NT NT B NT 1H~1,2,4—triazoI—1—y|)~2— (furan-3—y|)acrylate (E)—3—(3—(3,5- ifluoromethyl)phenyl)— 123 NT NT D NT 1H—1,2,4—triazoi—1—yl)—2— (pyrimidin—S—yl)acrylic acid (E)-3—(3-(3,5— bis(trifluoromethyl)phenyl)— F30 1H—1,2,4—triazoI—1—yl)—2- (pyrimidin—S-yl)acrylamide (E)—3—(3—(3,5— bis(trifiuoromethy|)phenyl)— 125 NT NT D NT F30 1H-1,2,4—triazol—1—yl)—2—(5— fluoropyridin-S—yl)acryiic acid F3 _.____fi_+_____4 (E)—3—(3—(3,5— bis(trifluoromethy|)phenyl)— FSC 1H—1,2,4—triazo|—1-y|)-2—(5- fluoropyridin—S—yl)acry|amide (E)—3—(3—(3,5— bis(trif|uoromethy|)pheny|)— 127 B NT 1H—1,2,4—triazoI-1—yi)~2-(6— methoxypyridin—S— y|)acryiamide F3 i__|__ Cmpd. MT!" MTI' MT!" Structure RevGFP Name No. (2138) (MMIS) (3T3) <3-(3,s— N’% bis(trifluoromethyl)phenyl)— 128 ’(2 \ o NT NT D NT F30 1H—1,2,4—triazoI—l—yl)-2— (furany|)acrylic acid __F3___l__________ (E)—3—(3-(3,5- N’K:% bis(trifluoromethy|)pheny|)— 129 o F30 Hf \ NT NT B NT 1H—1,2,4—triazoI—1—y|)—2— (furan—3—yl)acrylamide F3 ___._______________________l o isopropyl (E)—3—(3—(3,5— —" bis(tr'|f|uoromethy|)pheny|)— 130 / B NT A NT ,4—triazoI—l—y|)—2—(1— F C / 3 \‘N N N’ \ methyl—1H—pyrazoI—4— y|)acry|ate OH (E)—3-(3—(3,5— __ bis(trifluoromethy|)pheny|)— N_N _ 131 I p30 /) \ ,N\ NT NT B NT lH—l,2,4-triazoI-1—yl)—2—(1— N N methyl-1H—pyrazol—4— y|)acrylic acid , (E)—3—(3—(3,5— N’N / \ bis(trifluoromethy|)phenyl)— 132 I N) N A A A D F30 .— 1H—1,2,4—triazol—l—yI)-2—(5— F fluoropyridin—3-y|)acry|amide * (E)—3—(3—(3,5— N’ / \ bis(trifluoromethy|)pheny|)— 133 F30 ’ N) NT A A C "N 1H-1,2,4—tr'lazol—1—yl)—2— (pyridazin—4—y|)acrylamide F3 "— l__ ._ (E)—3—(3—(3,5- N’N N / bis(trifluoromethy|)pheny|)— 134 F30 ’ \ F NT B A B N/ _ 1H—1,2,4—triazoI—1—yI)—2—(6— fluoropyridin—Z—y|)acrylamide _J_ Fs ———|———L——————————--J ~114— Cmpd. MTT MTT MTT Structure RevGFP Name No. (2138) (MMls) (3T3) (E)—3-(3—(3,5— 135 / \ bis(trifluoromethyl)phenyl)— F30 I N) NT B A D 1H—1,2,4—triazo|—1—yl)—2—(2— fluoropyridin—3—y|)acrylamide F3 _____l_______.____________ (E)—2—(2—aminopyrimidin—S- yl)—3—(3—(3,5— 136 F30 // /_\< B B A D bis(trifluoromethyl)phenyl)- 1H~1,2,4-triazol—l— NHZ y|)acrylamide [_____________,_O______._______._______F__________._NH2 (E)—3—(3—(3,5— bis(trifluoromethyl)phenyl)— 137 F30 l 9 / \N A B A D 1H—1,2,4—triazol—l-y|)—2-(2— N N" fluoropyrimidin—S- F y|)acry|amide _ F (E)—3—(3—(3,5- N—N bis(trifluoromethy|)phenyl)— 138 / N) / \ F30 A A A B 1H—1,2,4—triazol-1—yl)~2—(3— fluoropyridin—4—yl)acrylamide _ (E)-3—(3—(3,5— N— / \ bis(trifluoromethyl)pheny|)- 139 FBC I NT B B D .. ,4—triazoI—l—yl)—2—(6— F fluoropyridin-3—y|)acrylamide ______,_ NH2 _‘ - (E)(3-(3,5- / \ bis(trif|uoromethy|)phenyl)— 140 F30 ’N) F A A A D ,4—triazoI—l-yl)-2—(2— pyridin—4—y|)acrylamide F3 4 _ (E)—3—(3—(3,5— N"N bis(trif|uoromethyl)phenyl)- 141 ’N) / \ C' B B A D F30 lH—l,2,4—triazol—1—yl)—2—(5— chloropyridin—3—yl)acry|amide F3 __J 2014/043479 -115— Cmpd. MTT MTT MTT ure RevGFP Name NO. (2138) (MMlS) (3T3) (E)-3—(3—(3,5— N—- bis(trifluoromethyl)phenyl)— 143 F30 I) /\ lH—l,2,4—triazoI—1—y|)-2—(6— chloropyridin—3—yl)acry|amide (E)—3—(3-(3,5— bis(trifluoromethyl)phenyl)— 144 F3C I NT 1H—1,2,4—triazoI—1—y|)—2—(2— chloropyridin—3—yl)acrylamide (E)—3—(3—(3,5— bis(trifluoromethyl)pheny|)— 145 F30 I NT lH—l, 2,4—triaZOI—1—yI)—2—(2,6— difluoropyridin—3— y|)acrylamide (E)(3-(3,5— bis(trifluoromethy|)pheny|)— 146 NT lH—l,2,4—triazol—1—yl)-2— phenylacrylamide (E)-3—(3—(3,5— ifluoromethy|)pheny|)- 147 F30 lH—l, 2,4—triazoly|)—2—(2— (trifluoromethyl)pyridin-4— yl)acrylamide _]_____ (E)—3—(3—(3,5— bis(trifluoromethyl)phenyl)— lH—l,2,4—triazoI—1—yl)—2—(5— cyanopyridin—3—yl)acrylamide (E)—3—(3—(3,5— bis(trifluoromethyl)pheny|)— lH-l,2,4—triazol-1—y|) (quinolin—3-yl)acrylamide —ll6- Structure Name (E)~3—(3—(3,5— bis(trifluoromethy|)phenyl)— 1H—1,2,4—triazol—1—yI)—2—(2— fluorobiphenyl—4— yl)acry|amide (El ifluoromethyl)phenyl)— 151 F30 / /) NT C B D 1H—1,2,4—triazol—1—yl)—2—(4— N (pyridin—3— / \N yl)phenyl)acry|amide F3 — O _._____________ _. (El N— bis(trif|uoromethy|)phenyl)— 152 Fae ’ /) D NH NT B B 1H—1,2,4—triazol—l—yl)-2—(1H— indazol—6—yl)acry|amide F3C J‘m (Z)(3-(3,5- \ N bis(trifluoromethyl)phenyl)— 153 Nr N \ NT B A D ’ 1H—1,2,4~triazol—l—yl)—2— Fe NHZ (pyrimidin—S—yl)acrylamide /N F F30 (Z)—3—(3—(3,5— Ni \ bis(trifluoromethy|)phenyl)— 154 NT NT B NT 1H—1,2,4—triazol—l—yI)—2—(6— 0 F39%j \ NH2 +fluoropyridin—3-yl)acrylamide(Z)—3—(3-(3,5— bis(trif|uoromethyl)phenyl)— 1H-1,2,4—triazol—1—y|)—2-(2— fluoropyridin—4—yl)acrylamide (Z)-3—(3—(3,5- bis(trifluoromethyl)phenyl)— 1H—1,2,4—triazol—1—yl)—2-(6~ chloropyridin—3—yl)acrylamide (Z)—3—(3—(3,5— ifluoromethy|)pheny|)— 1H—1,2,4—triazol—1—yl)—2—(2— fluoropyridin—3-yl)acrylamide ] Compound 124 was r tested against a panel of selected solid and hematological cancer cell lines and selected normal cell lines in an MTT assay. Briefly, the various cell lines above were plated at different densities on day 1. After 24 hours of growth, cells were treated with dose curves (10 uM start with 1:3 dilutions) of Compound 124 in duplicate rows. Cells and Compound 124 were incubated in a 37 °C incubator for 72 hours. -ll7- Cell Titer AQueous One was added to each well, and the plates were read in a plate reader at OD 495.

Hematological cancer cell lines tested ed MOLT-4, Z—138, THPl, MO7E, OCIAML—5, AML—l93, Daudi, , TF-l, Farage, Pfieffer, MV—4-ll, MINO, HEL.92.1.7, KG-l, BL—2, MMlR, HS—Sultan, RL, U-937, DB, BL—40, U—266 and ANBL—6.

Solid cancer cell lines tested included PATU-8902, SK-CO—l, NCI—H2170, PL—45, NCI- H1650, TFK-l, NCI-H520, RKO, U118 MG, HeLa, HuCCT—l, CAPAN~1, NCI—H889, NCI— H187, L3.6pl, HEP 3B, M8751, 9, AU—565, SHSY5Y, Tera-1, SW—620, PC3, LS— 180, SW—48, NCI—H1299, Colo-205, NCI-H28, HT1080, SHP—77, MSTO—211H, LoVo, HCT-15, NCI—H2030, Calu—6, Calu-3, SW-403, HPAC, NCI-H1563, PATU—8988T, PATU- 8988S, HPAF—II, Colo—201,NCI~H747, , HCC—4006, NCI—H358, HCC~827, PANC— .05, SW~948, SW—480, SW~1417,DLD-1, SW-1116, MDA—MB—231,NCI—H508,MCF7, LN-18, NCI-H820, HCC—2935, 8, 122, NCI-H226, LS—l74T, HCT116, MDA~MB-36l, SW-900, NCI-Hl993, .1, C6, MHCC97H and SKOV3. Normal cell lines tested included IMR—90 and 3T3. The results of further testing of Compound 124 are reported in Table 2. -118— Table 2.

Cell line Cmpd 124 (UM) 0.14 0.15 0.15 0.22 0.23 MO7eMTT HEL.92.1.7MTT 0.23 0.25 O (.0 0.31 0.34 SMTT U118MGMTT 0.37 0.0 ##- 0.41 HS-SultanMTTm PATU-8902MTT 0.41 MSTO-211HMTT NCl-H358MTT 0.42 0.42 0.43 0.45 0 0.46 Farage M TT 0.46 HOT-15 M TT 0.46 L3.6p| MTT 0.47 AU-565 MTT 0.49 SW~837 M TT .0 U1 2014/043479 Cmpd124 3.4 .

Cys 528 Mutation Assay U2OS sarcoma) cells stably expressing GFP—tagged HIV—Rev fused to the CAMP—dependent protein kinase inhibitor (PKI) nuclear export signal (Rev—GFP) were transiently transfected with constructs expressing wild—type CRMl or mutant CRMl— 8er for 36 hours. The transient transfection efficiency in the experiment was estimated to be 50%. When Rev—GFP and wild—type CRMl were co—expressed in the cells and the cells were treated with 30 uM nd 124 for 4 hours, Rev-GFP was localized to the cell nucleus and nucleolus. However, when Rev—GFP and mutant CRM-Cys5288er were co-expressed in cells, treatment of the cells with 30 uM Compound 124 did not induce nuclear localization of Rev-GFP. The 30 uM Compound 124 treatment was chosen to maximize drug exposure on the transfected cells. These s demonstrate the importance of Cys528 for CRMl inhibition by Compound 124.

Washout Assay U2OS cells stably expressing a green cent protein—tagged HIV-Rev fused to the ependent PKI r export signal (Rev-GFP) were used to evaluate the level of CRMl inhibition and the resulting IC50 of Compound 124 with or without washing the compound out after ent. Three 96—well plates of U2OS Rev—GFP cells were treated with Compound 124 (that had been serially diluted 1:3 starting at 10 HM) or DMSO for 4 hours. After 4 hours, one of the plates was fixed with PFA (no washout, condition A).

Media was removed from the other two plates, and the cells were washed twice with fresh media and incubated further in media that did not contain Compound 124. A second plate was fixed with PFA after a 4 hour washout (4 hr washout, condition B) and a third plate was fixed with PFA after a 24 hour washout (24 h washout, condition C). Cells were counterstained with the nuclear dye DAPI. The leos of Compound 124 under condition A, ion B and ion C were determined, and are reported in Table 3. Table 3 shows that Compound 124 is still very effective following a 4 hour washout, and ses only 6— fold after a 24 hour washout. These results confirm that Compound 124 covalently binds to XPOl.

Table 3. 4 h treatment + 4 h treatment + 4 h treatment + no washout 4 h washout 24 h washout Com ound 124 1C50 310 nM XPO] Cargo Localization Assay U2OS cells were treated with 500 nM Compound 124 for 4 to 24 hours and either fixed with 100% ld methanol (MeOH) and bilized/blocked with 0.1% Tween , 0.3 M glycine, and 1% BSA in PBS or fixed with PFA (3% paraformaldehyde and 2% sucrose in PBS) and permeabilized/blocked with 0.1% Triton-X100 and 1% BSA in PBS.

The fixed cells were analyzed by immunofluorescence (IF) for the nuclear localization of the following XPOl cargo proteins: p53, IKB, FoxolA, PP2A, p21 and p27. Nuclei were stained with DAPI. Images were taken at 20X magnification. The images of cells treated with Compound 124 showed increased or complete nuclear localization of XPOl cargoes. -l2l- XPOI Degradation Assay HT1080 (fibrosarcoma) cells were treated with five ent concentrations of Compound 124 for 24 hours. Western blot analysis of cellular lysates of the treated cells was used to determine the protein expression of XPOl. Beta-actin was used as a g control. is an image of a Western blot obtained from this experiment, and shows that Compound l24 degraded XPOl in a dose—dependent manner.

Example 3. en antibody—induced arthritis (CAIA) Mouse Model Compound 124 was evaluated in an anti-collagen antibody—induced mouse model of rheumatoid arthritis. Specifically, twenty-four (24) male Balb/c mice, aged 6 to 7 weeks, were randomly ed to 3 groups that would receive vehicle, Compound 124 at 20 mg/kg or Compound 124 at 40 mg/kg. On study Day 0 (study commencement), all mice were subjected to a 4 mg intravenous injection of ArthritoMAbTM antibody cocktail (MD ences #51306001), followed by an eritoneal injection of LPS (SOug/mouse) on study Day 3. The mice began treatment on Day 6, when the average clinical scores d 2.

Treatment with Compound 124 was given PO, twice a week (Mondays and Wednesdays) up until Day 17.

The animals were examined for signs of arthritis on study Day 0 in all paws (front left and right paws, hind left and right paws). The signs of arthritis on study Day 0 served as a baseline for the arthritis clinical score ter. Arthritic responses were examined daily from Day 3 until Day 8, and on Days 10, 12, 15 and 18 (study termination). Arthritis reactions were reported for each paw according to a 0-4 scale in ascending order of severity as shown in Table 4.

Table 4. Arthritis clinical score Arthritis Score No on, normal Mild, but definite redness and swelling of the ankle/wrist or apparent redness and swelling limited to individual digits, regardless of the number of affected digits Moderate to severe s and swelling of the ankle/wrist Redness and swelling of the entire paw including digits Maximally inflamed limb with involvement of multiple joints —122l al signs data are presented as means :1: SEM (standard error of the mean).

Treatment groups 2-3 were compared to vehicle group 1 using one-way ANOVA test followed by Tukey post-test. A p value of <0.05 is considered to represent a significant difference.

On study Day 6, 88% of the animals d with vehicle showed clinical signs of tis. At the end of the study, this value decreased to 75%. The percentage of animals that showed clinical signs of arthritis and were treated with Compound 124 at a dose of 20 mg/kg was reduced from 78% on study Day 6 to 22% on study Day 18. The percentage of animals that showed clinical signs of arthritis and were treated with Compound 124 at a dose of 40 mg/kg was reduced from 88% on study Day 6 to 13% on study Day 18. is a graph of mean clinical score for all paws in the CAIA mouse model of rheumatoid tis as a function of study day. shows that ent with Compound 124 reduced arthritis scores of mice in the study compared to vehicle treatment.

In conclusion, treatment with 20 mg/kg or 40 mg/kg Compound 124 reduced the number of animals expressing disease, as well as the tis scores of the animals in this study.

Example 4. Xenograft Models Compound 124 and Compound 149 were evaluated in several xenograft models in mice.

The oncological impact of Compound 124 and Compound 149 was evaluated using an MDA-MB-468 (triple negative breast cancer) xenograft model in CB-17 SCID mice.

MDA-MB-468 (ATCC # HTB-102) breast adenocarcinoma cells were obtained from ATCC.

These cells were grown in high glucose DMEM medium mented With 10% fetal bovine serum, 1% penicillin and streptomycin, and 2mM amine. Cells were sub— cultured by dilution at a ratio of 1:4. MDA-MB—468 cells were harvested by trypsinization and counted using a hemocytometer. Cells were ended in PBS at a concentration of 4 X 108 cells per mL. Cells were placed on ice and mixed with an equal volume of Matrigel (BD Biosciences CB-40234). Twenty-two (22) CB-17 SCID mice were inoculated sub- cutaneously in the left flank with 4 x 107 -468 cells. Treatment was initiated when the tumors reached a mean volume of ~1 00 m3. Mice were allocated to three (3) groups of eight (8) mice for the vehicle and seven (7) mice for each treatment group — Compound 124 and Compound 149 — such that mean tumor volume was ~100 mm3 in each group. Mice were treated with e, Compound 124 or Compound 149. Compound 124 (10 mg/kg) and Compound 149 (10 mg/kg) were given orally (PO) once daily every day of the week.

Animals’ weights and condition were recorded daily, and tumors were measured on Mondays, Wednesdays, and Fridays. is a graph of mean tumor volume as a function of time, and shows that mean tumor volume was reduced in mice bearing an MDA-MB-468 xenograft and treated with Compound 124 or Compound 149 compared to mice bearing an -468 xenograft and d with vehicle.

In another study, the impact of Compound 124 on tumor growth was tested using a Z—138 mantle cell lymphoma cancer xenograft model in SCID mice. Z-138 (ATCC # CRL- 3001) mantle cell lymphoma cells were obtained from ATCC. These cells were grown in IMEM medium supplemented with 10% horse serum, 1% penicillin and streptomycin, and 2mM L—glutamine. Cells were sub-cultured by dilution at a ratio of 1:5 to 1:10. Z—138 cells were harvested by centrifugation and counted using a hemocytometer. Cells were resuspended in PBS at a concentration of 2 x 108 cells per mL. Cells were placed on ice and mixed with an equal volume of Matrigel (BD Biosciences 34). This e was kept on ice and injected into the left flank of mice in a volume of 0.2 mL, equivalent to 2 x 107 cells per mouse. Thirty-two (32) CB-17 SCID mice were inoculated subcutaneously in the left flank with 2 x 107 Z-138 cells. Treatment was initiated when the tumors reached a mean volume of 125.2 mm3. Mice were allocated to four (4) groups of eight (8) mice such that mean tumor volume in each group was within the range of 106.5 to 138.8 mm3 . Mice were treated with vehicle, standard of ositive control drug (cyclophosphamide) or nd 124 (5 mg/kg or 15 mg/kg). Compound 124 (5 or 15 mg/kg) was given orally (PO) daily beginning on Day 1. Animal weights and conditions were recorded daily, and tumors were measured on Mondays, Wednesdays and Fridays. is a graph of mean tumor volume as a function of time, and shows that mean tumor volume was reduced in mice bearing a Z-13 8 xenograft and treated with Compound 124 compared to mice bearing a Z-138 xenograft and treated with vehicle.

Results obtained from the 15 mg/kg dose of Compound 124, in ular, compared bly with the results obtained using cyclophosphamide. -124— In yet another study, the effects of Compound 124 on tumor growth were evaluated using a Hep3B hepatocellular carcinoma xenograft model in SCID mice. Hep 3B cells (ATCC# HTB- 8064) hepatocellular carcinoma cells were obtained from ATCC. These cells were grown in DMEM medium mented with 10% fetal bovine serum, 1% penicillin and omycin. Cells were sub-cultured by dilution at a ratio of 1:4. Hep3B cells were harvested by centrifugation and counted using a hemocytometer. Cells were resuspended in PBS at a concentration of 5 X 107 cells per mL. Cells were placed on ice, and then mixed with an equal volume of MatrigelTM (BD Biosciences CB—40234). This mixture was kept on ice and injected into the left flank of mice in a volume of 0.2 mL, equivalent to 5 x 106 cells per mouse. Thirty-two (32) SCID mice were inoculated subcutaneously in the left flank with 5 x 106 Hep 3B cells. ent was initiated when the tumors reached a mean volume of 103.7 mm3 ard deviation i 30 mm3, range 17-183 mm3). Mice were allocated to four (4) groups of eight (8) mice such that mean tumor volume in each group was within the range of 95 to 104 mm3. Mice were treated with vehicle, standard of care control (doxorubicin), or Compound 124 (5 mg/kg or 15 mg/kg). With the exception of doxorubicin (which was given 1P), all compounds were given by oral gavage. Compound 124 (5 or 15 mg/kg) was given orally (PO) daily. Animal weights and conditions were ed daily, and tumors were ed on s, Wednesdays and Fridays. is a graph of mean tumor volume as a function of time, and shows that mean tumor volume was reduced in mice bearing a Hep 3B xenograft and treated with Compound 124 compared to mice bearing a Hep 3B xenograft and treated with vehicle. The results obtained from ent with nd 124, particularly the 15 mg/kg dose of Compound 124, compared favorably with the results obtained using doxorubicin.

In another study, the effects of Compound 124 on tumor growth were evaluated using a COLO 205 colorectal carcinoma xenograft model in SCID mice. COLO 205 (CCL- 222) colorectal cancer cells were obtained from ATCC. These cells were grown in RPMI— 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin and omycin.

Cells were sub—cultured by transferring floating cells to a new flask and trypsinizing adherent cells before sub—culturing at a ratio of 1:4. COLO 205 cells were harvested by centrifugation and counted using a hemocytometer. Cells were resuspended in PBS at a tration of 5 X 107 cells per mL. Cells were placed on ice, and then mixed with an equal volume of MatrigelTM (BD Biosciences CB—40234). This mixture was kept on ice and injected into the 2014/043479 —125— left flank of mice in a volume of 0.2 mL, equivalent to 5 x 106 cells per mouse. Thirty—two (32) SCID mice were inoculated subcutaneously in the left flank with 5 X 106 COLO 205 cells. Treatment was initiated when the tumors reached a mean volume of 103 .7 mm3 (standard deviation :: 30 mm3, range 17-183 mm3). Mice were allocated to four (4) groups of eight (8) mice such that mean tumor volume in each group was within the range of 95 to 104 mm3. Mice were treated with vehicle, standard of care control (5—FU, 5-fluorouracil) and Compound 124 (5 mg/kg or 15 mg/kg). With the exception of 5—FU (which was given 1P on days 1 and 3), all compounds were given by oral gavage. nd 124 (5 or 15 mg/kg) was given orally (PO) daily. Animal s and conditions were recorded daily, and tumors were measured on s, Wednesdays and Fridays. is a graph of mean tumor volume as a function of time, and shows that mean tumor volume was d in mice bearing a COLO 205 xenograft and treated with Compound 124 ed to mice bearing a COLO 205 xenograft and treated with vehicle.

The results obtained from treatment with Compound 124, particularly the 15 mg/kg dose of Compound 124, compared favorably with the results obtained using 5-FU.

In another study, the s of nd 124 on tumor growth were evaluated using a MOLT 4 acute lymphoblastic leukemia xeno graft model in SCID mice. MOLT 4 (CRL—1582) acute lymphoblastic leukemia cells were obtained from ATCC. These cells were grown in RPMI—1640 medium supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin. Cells were sub—cultured by transferring floating cells to a new flask and trypsinizing adherent cells before subculturing at a ratio of 1:4. MOLT 4 cells were harvested by centrifugation and counted using a hemocytometer. Cells were resuspended in PBS at a concentration of 5 x 107 cells per mL. Cells were placed on ice, and then mixed with an equal volume of MatrigelTM (BD Biosciences CB-40234). This mixture was kept on ice and injected into the left flank of mice in a volume of 0.2 mL, equivalent to 5 x 106 cells per mouse. Thirty—two (32) SCID mice were inoculated subcutaneously in the left flank with 5 x 106 MOLT 4 cells. Treatment was initiated when the tumors reached a mean volume of 106.5 mm3 (standard deviation :: 33.9 mm3, CV 31.9%, range 43—181 mm3). Mice were allocated to four (4) groups of eight (8) mice, one group of 5 mice and one group of four mice, such that mean tumor volume in each group was within the range of 102 to 111 mm .

Mice were treated with vehicle, standard of care control (doxorubicin 5 mg/kg IP Days 1 and 15) or nd 124 (5 mg/kg or 15 mg/kg). With the exception of doxorubicin (which was given -126~ IP), all nds were given by oral gavage. Compound 124 (5 or 15 mg/kg) was given orally (PO) daily. Animal weights and conditions were ed daily, and tumors were measured on Mondays, Wednesdays and Fridays. is a graph of mean tumor volume as a function of time, and shows that mean tumor volume was reduced in mice bearing a MOLT 4 xenograft and treated with nd 124 compared to mice bearing a MOLT 4 xenograft and treated with vehicle.

Example 5. astoma Cells (U87MG and U251MG) were detached and re-suspended at 1x105 cells/mL. ,000 cells were loaded into a hanging drop plate (3D Biomatrix Cat. No.: HDP1096) and incubated for 5 days (37 0C; 5% C02) to form spheroids. 300 uL of Matrix Gel (Corning Matrigel Cat# 354234; Lot# 2) were plated per well in a 24-well plate and incubated for 30 minutes. Spheroids were removed from the hanging drop plate and seeded into the MATRIGELTM (1 spheroid per well). Spheroids were incubated for 15 minutes and then 460 uL media was added. After overnight incubation of the ids, 1 uM Compound 124 was added to a final volume of 1 mL/well. The plates were analyzed at several time points using 40X and 20X phase copes, and photos of the spheroids were taken. are images of U87MG and U251MG control spheroids and U87MG and U251MG spheroids treated with 1 uM Compound 124, and shows the effects of treatment with Compound 124 on two glioblastoma cell lines, The U87MG spheroids treated with nd 124 (1 uM) demonstrated a significant reduction in cell growth as compared with the control, without showing any spreading or growth of the cells out of the sphere. In the U251 spheroids treated with Compound 124, however, in addition to the significant reduction in cell growth as compared with the control, shrinking of the spheroid with complete elimination of any cell growth out of the sphere was noted. Based on microscopic analysis, te destruction of these cells was observed.

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The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

While this invention has been particularly shown and described with references to example ments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims (39)

Claims:

1. A compound represented by structural formula IV: F3C O N NH2 N R2 F3C (IV), or a pharmaceutically acceptable salt thereof, wherein: 5 R2 is selected from optionally substituted heteroaryl having 5 to 15 ring atoms and optionally substituted aryl having 6 to 12 ring atoms, wherein the optional substituents on R2 groups are 1, 2 or 3 substituents independently selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 , C1-C4 koxy, hydroxyl, amino, C1-C4 alkylamino, C1-C4 dialkylamino, 10 sulfhydryl, cyano, C6 aryl and heteroaryl having 5 or 6 ring atoms.

2. The compound of claim 1, wherein R2 is an optionally substituted heteroaryl having 5 to 15 ring atoms.

3. The compound of claim 1 or 2, wherein R2 is an optionally substituted 5 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the 15 group consisting of nitrogen, oxygen and sulfur.

4. The compound of claim 3, wherein R2 is an ally substituted 5-membered heteroaryl having 1, 2 or 3 heteroatoms independently ed from the group consisting of nitrogen, oxygen and .

5. The compound of claim 4, wherein R2 is an optionally substituted pyrrolyl, furanyl, 20 thiophenyl, pyrazolyl, imidazolyl, thiazolyl, azolyl, oxazolyl, olyl, triazolyl, thiadiazolyl, or oxadiazolyl.

6. The compound of claim 3, wherein R2 is an optionally substituted 6-membered heteroaryl having 1, 2 or 3 heteroatoms ndently selected from the group consisting of nitrogen, oxygen and sulfur. 25

7. The compound of claim 6, wherein R2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl.

8. The compound of claim 1, n R2 is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C1-C4 alkyl, -CF3, amino and cyano.

9. A compound represented by any one of the following structural formulas: N N F3C N F3C F N N F3C Cl N N O O NH2 NH2 N N N N F3C N F3C N N N CF3 F3C O O NH2 NH2 N N N N F3C F3C N N N N CF3 F3C (22904663_1):KZA F3C N O O NH2 NH2 N N N F3C F3C N N CF3 F3C O O O NH2 NH2 N N N N N N F3C F3C F3C CF3 N N N N N N CF3 CF3 F3C F3C CN N N O O NH2 NH2 N N N N F3C F3C N N N CF3 F3C O O NH2 NH2 N N S N N F3C N F3C F N N CF3 F3C 663_1):KZA O O NH2 NH2 N N N N F3C F3C NH N N CF3 F3C O O NH2 NH2 F3C N N N N N N N F3C N F3C N N N N N N N F3C O NH2 CF3 F3C F3C N F N N N F3C F N N N F3C O NH2 F F3C N N N N F3C N N F N N F3C O NH2 F3C Cl N N F3C N N N N N O NH2 NH2 F3C H2N O O NH2 F3C F N N N N N F3C O F3C N N N N N N N F F3C O NH2 CF3 F3C or a pharmaceutically able salt of any of the foregoing. (22904663_1):KZA

10. The compound of claim 9, ed from: F3C N N N N N F3C N F3C F N N O O O NH2 NH2 NH2 N N N N N N F3C N N F3C F3C Cl N N N N N CF3 CF3 F3C F3C N (22904663_1):KZA O O NH2 NH2 N N N F3C F3C N N N CF3 F3C O O NH2 NH2 N N N N F3C F3C N N N N CF3 F3C O O NH2 NH2 N N N N F3C F3C N N N CF3 F3C O O N N N N O F3C F3C CF3 N N N CF3 F3C F3C CN N N O O NH2 NH2 N N N N F3C N F3C N N N N CF3 F3C O O NH2 NH2 N N N N F3C F3C F N N CF3 F3C 663_1):KZA O O NH2 NH2 N N N N F3C N F3C N N N F3C F3C O O NH2 NH2 N N N N N F3C F F3C NH N N F3C F3C H2N O O NH2 N N N N F3C O F3C N N N N CF3 F3C F3C N N N or a pharmaceutically acceptable salt of any of the foregoing, wherein the exocyclic double bond is in a trans configuration.

11. The compound of claim 9, ed from: F3C N N N S N F3C N N F F3C O NH2 F3C N F3C Cl N N N N N N N N F3C O NH2 F3C O NH2 (22904663_1):KZA F3C N F F3C F N N N N N F3C O NH2 N F3C O NH2 or a pharmaceutically able salt of any of the foregoing, wherein the exocyclic double bond is in a cis configuration.

12. A ceutically acceptable composition comprising a compound of any one of the preceding claims, or a ceutically acceptable salt thereof, and a 5 pharmaceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the cture of a medicament for treating a disorder associated with CRM1 ty.

14. The use according to claim 13, wherein the disorder is selected from a proliferative 10 disorder, cancer, an inflammatory disorder, an autoimmune disorder, a viral ion, an ophthalmological disorder, a neurodegenerative er, a disorder of al tissue growth, a disorder related to food intake, an allergy, and a atory disorder.

15. The use according to claim 14, wherein the disorder is cancer. 15

16. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for promoting wound healing in a subject.

17. The use according to claim 15, wherein the cancer is selected from acute monocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, erythroleukemia, 20 megakaryoblastic leukemia, histiocytic lymphoma, non-Hodgkin's B-cell lymphoma, breast cancer, bronchioalveolar carcinoma, al carcinoma, colorectal cancer, embryonal carcinoma, extrahepatic bile duct carcinoma, glioma, hepatocellular carcinoma, non-small cell lung cancer, small cell lung carcinoma, liver bile duct carcinoma, multiple myeloma, myelomonocytic cancer, 25 mesothelioma, neuroblastoma, ovarian cancer, pancreatic adenocarcinoma, and rectum adenocarcinoma.

18. The use according to claim 15, wherein the cancer is selected from mantle cell lymphoma, B-cell leukemia, Burkitt’s lymphoma, and diffuse large B-cell lymphoma.

19. The use according to claim 15, wherein the cancer is selected from osteosarcoma, 5 triple negative breast , mantle cell ma, hepatocellular carcinoma, colorectal cancer, acute lymphoblastic leukemia and glioma.

20. The use according to claim 15, wherein the cancer is leukemia.

21. The use according to claim 20, wherein the leukemia is selected from hairy cell leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute 10 myeloid leukemia and chronic lymphocytic leukemia.

22. The use according to claim 15, wherein the cancer is lymphoma.

23. The use of claim 22, wherein the lymphoma is ed from cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma. 15

24. The use ing to claim 15, wherein the cancer is a solid cancer.

25. The use according to claim 24, wherein the solid cancer is selected from te cancer, breast cancer, liver cancer, colon cancer, pancreatic cancer, renal cancer, lung, penile cancer, nasopharyngeal carcinoma and ovarian cancer.

26. The use according to claim 17, wherein the cancer is multiple myeloma. 20

27. The use according to claim 15, wherein the ment comprises a therapeutically ive amount of a compound represented by F3C N N N or a ceutically acceptable salt thereof.

28. The use according to claim 17, wherein the cancer is colorectal cancer.

29. The use according to claim 28, n the medicament comprises a therapeutically effective amount of a compound represented by F3C N N N 5 or a pharmaceutically acceptable salt thereof.

30. The use according to claim 15, wherein the cancer is prostate cancer.

31. The use according to claim 30, wherein the ment comprises a therapeutically effective amount of a compound represented by F3C N N N 10 or a pharmaceutically acceptable salt thereof.

32. The use according to claim 13, wherein the disorder is myelodysplastic syndrome.

33. The use according to claim 32, wherein the medicament comprises a therapeutically effective amount of a compound represented by F3C N N N 15 or a pharmaceutically acceptable salt thereof.

34. The use ing to claim 25, wherein the cancer is penile cancer.

35. The use according to claim 34, wherein the medicament comprises a therapeutically ive amount of a compound represented by F3C N N N or a pharmaceutically acceptable salt thereof. 5

36. The use according to claim 25, wherein the cancer is nasopharyngeal carcinoma.

37. The use according to claim 36, wherein the medicament ses a therapeutically effective amount of a nd represented by F3C N N N or a pharmaceutically acceptable salt thereof. 10

38. The use according to any one of claims 13 to 37, wherein the ment is formulated for oral composition.

39. The compound of claim 1, represented by the following structural formula or a pharmaceutically acceptable salt thereof. 15 Karyopharm Therapeutics Inc. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: